Sulfonamides derived from benzocyclic or benzoheterocyclic acids, their preparation and application in therapeutics

ABSTRACT

The invention relates to new sulphonamide derivatives of benzo-cyclic or benzo-heterocyclic acids and their derivatives of general formula I ##STR1## in which: R represents a straight-chain or branched lower alkyl radical having 1 to 9 C; 
     a phenyl radical which is unsubstituted or substituted by one or more groups: 
     straight-chain or branched lower alkyl having 1 to 4 C, halogeno, alkoxy, nitro, amino, dialkylamino or CF 3  ; 
     a substituted or unsubstituted naphthalene; 
     a thiophenyl radical; 
     R 1  represents a hydrogen or a straight-chain or branched lower alkyl or a benzyl; 
     R 2  represents a hydrogen, a straight-chain or branched lower alkyl group, a substituted or unsubstituted phenyl group or an aralkyl group; 
     R 3  represents a hydrogen or a straight-chain or branched lower alkyl (1 to 6 C); 
     --X-- represents a divalent functional radical chosen from the following: --CH 2  --; ##STR2## where R 4  =H or Me; A represents a benzo-cyclic or benzo-heterocyclic divalent radical chosen from the following (a) to (j): ##STR3## and n can assume the values 1 to 4 inclusive; and the therapeutically acceptable organic or inorganic salts (R 3  =H), the pure isomers or diastereoisomers or their mixture and all the pharmaceutical compositions of formula I with other active principles. 
     The invention relates to the application of I as a medicament and the preparation processes.

The present invention, made at the Centre de Recherche PIERRE FABRE(Pierre Fabre Research Center) relates to new sulphonamides, theirpreparation and their application as a medicament.

Platelet anti-aggregants--the essential activity of which is to combatthrombosis--are increasingly being used either for preventive purposesor as therapeutic adjuvants in this indication as well as in angina,myocardial infarction, atheroma and cardiac ischemia. Thromboxane A₂(TxA₂) is the mediator most frequently involved in platelet aggregationand is the most powerful proaggregant agent which forms in the course ofa metabolization path from arachidonic acid at the platelet level (F.Numano, Atherosclerose and antiplatelet therapy, Drugs of Today, 21, 41,1985). In physiological disorders, the action of TxA₂ can be stoppedduring various stages of its formation and, in particular, by inhibitingeither its synthesis or its action, by blocking the TxA₂ receptorscausing aggregation.

The research on molecules antagonizing the TxA₂ receptors is a recentand promising approach for combating the damage caused by this.(Antithrombotic Agents, M. KUCHAR and V. REJMOLEC, Drug of the Future11, 689, 1986; Comparison of the action of TxA₂ receptor antagonists, A.M. LEFER, Drugs of Today 21, 283, 1985).

The compounds of the present invention have the general formula I##STR4## in which: R represents a straight-chain or branched lower alkylradical containing from 1 to 9 C and, by way of non-limiting example:Me, Et, Pr, Bu, iBu . . . ;

a phenyl radical which is unsubstituted or substituted by one or moregroups: lower alkyl (1 to 4 C) or halogen or alkoxy, trifluoromethyl,nitro, amino, lower dialkylamino (1 to 4 C) and, by way of non-limitingexample: Me, Et, i-Pr, F, Cl, Br, MeO, EtO, NO₂, NH₂, NMe₂, CF₃ ;

a naphthyl radical which is unsubstituted or substituted as above; or athiophenyl radical;

R₁ represents a hydrogen or a straight-chain or branched C₁₋₄ loweralkyl, a benzyl and, by way of non-limiting example: Me, Et, i-Pr;

R₂ represents a hydrogen, a straight-chain or branched lower alkyl grouphaving 1 to 6 C and, by way of non-limiting example: Me, Et, i-Pr, i-Bu;

a phenyl group which is unsubstituted or substituted by a chlorine or amethoxy;

an arylalkyl group containing 7 to 9 carbon atoms;

R₃ represents a hydrogen or a straight-chain or branched lower (1 to 6C) alkyl and, by way of non-limiting example: Me, Et, i-Pr, i-Bu;

X represents a divalent functional radical chosen from the following:--CH₂ --; --CH--OR₄ ; --C=O; --C=N--OR₄ ;

and ##STR5## where R₄ =H or Me. A represents a benzo-carbocyclic orbenzo-heterocyclic bivalent radical chosen from the following (a) to(j): ##STR6## n=1 to 4 inclusive.

The present invention also includes the therapeutically acceptableinorganic or organic salts of compounds of the general formula I inwhich R₃ =H and, by way of non-limiting example, the sodium, calcium,zinc, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium andtris(2-hydroxyethyl)ammonium salts and also their hydrates whereappropriate and the hydrates of the precursor acids.

When the compounds of general formula I contain at least one asymmetriccarbon, the present invention also relates to the racemic mixtures andthe various enantiomers or diasteroisomers or their mixtures.

The present invention also relates to the use of the compounds ofgeneral formula I as a medicament and to the pharmaceutical compositionscontaining this medicament. The pharmaceutical compositions according tothe present invention can use one or more compounds of formula I, ifappropriate in combination with one or more other active principles.

Finally, the processes for synthesis of the compounds of general formulaI also form part of the present invention.

SYNTHESIS OF THE COMPOUNDS OF GENERAL STRUCTURE I

The base starting material for all of the syntheses is the ester of theacid in the 2- or 3-position of the indane derivative orbenzo-heterocycle envisaged (compound II), where A has the same meaningas in I, with the exception of the radicals b, e, h, and j, and where R₅has the same value as R₃ defined in I, with the exception of hydrogen.

In a first period, the compound II is subjected to a Friedel-Craftsreaction with the aid of a suitably substituted acid chloride of generalformula III, where n and R₂ have the same meaning as in the formula Iand where Y represents a halogen (bromine or chlorine) or analkoxycarbonylamino of formula R₈ OCONR₁ (where R₈ represents astraight-chain lower alkyl or a benzyl) to give the corresponding acylderivative IV (method A). ##STR7##

In a second period, the compound IV is reacted according to thesynthesis scheme I in the case where Y is a halogen (chlorine orbromine) or according to the synthesis scheme II in the case where Yrepresents an alkoxycarbonylamino to give the compounds of generalformula I, which are the subject of the present invention.

In these schemes the radicals have the same meaning as in I and the newgroups are defined in the synthesis scheme.

1) Case where Y represents a halogen (bromine, chlorine) in IV (scheme1)

The condensation reaction of IVa with sodium nitride in anaqueous-alcoholic mixture yields the compound V (method B), and thelatter compound is reduced with hydrogen in the presence of a catalystin an acid-alcoholic medium to give the esterified amino ketone in theform of a salt VI (hydrochloride for example) (method C). Thecondensation reaction of the above derivative VI with a suitablysubstituted sulphonyl halide of general formula VII

    R--SO.sub.2 --Z                                            VII

where R has the same meaning as in I and Z represents a chlorine or abromine or a fluorine, is effected using an organic base (pyridine forexample) to give the ester VIII of I where R₁ =H (method D). This estercan be saponified in a dioxane or alcohol/sodium hydroxide mixture togive the sulphamido-keto-acid IX of general formula I where R₁ and R₃ =H(method G). This keto-acid IX reacts with unsubstituted or substitutedhydroxyl-amines of formula

    R.sub.4 ONH.sub.2

under hot conditions in pyridine to give the corresponding oximes X(method H₁). The condensation reaction with an unsubstituted orsubstituted hydrazine of formula: ##STR8## in an organic acid under hotconditions leads to the corresponding hydrazone XI (method H₂). If thehydrogenation of compound V is continued further, it can lead to theamino-alcohol XII via the intermediate VI (method C). This amino-alcoholcan also be prepared from the ketone compound by reduction with aborohydride (Na or K) in an alcoholic medium (method E). It ispreferable to use the same alcohol as that of the ester function sinceif it is different the transesterified compound XII is obtained. Thehydroxysulphamido ester XIII can be obtained either from the ketonederivative IX by method E or by a condensation reaction of the sulphonylhalide of formula VII with the above amino compound XII (method D).Saponification of this compound carried out by method G gives thehydroxysulphamide acid XIV. The action of triethylsilane in atrifluoroacetic acid medium on the aminoketo ester VI enables thecarbonyl selectively to be reduced to methylene to give the amino esterXV (method F). This compound also forms according to method C in astrong acid medium (method N). The condensation reaction of XV with thecorresponding sulphonyl chloride (method D) gives the sulphamido esterXVI, which is saponified by the same method G to give the correspondingsaturated acid compound XVII. The latter can also be obtained from thecorresponding ketone derivative IX, either by reduction withtriethylsilane (method F) or by catalytic hydrogenation in a strong acidmedium (method M) or by reduction by the Clemmensen method in a nascenthydrogen medium (zinc/concentrated hydrochloric acid) in toluene (methodN). The dialkylation of XVII in the presence of halides (bromide,iodide) R₃ I or of the corresponding sulphate (R₃)₂ SO₄ leads, afterformation of the disodium derivative, to the esterified and N-alkylatedcompound in which R₁ =R₃ of formula XVIII (method L).

According to scheme I, the carbonyl in the intermediate IVa can bereduced to methylene to give the halogeno ester XIX, either with the aidof the Et₃ SiH/CF₃ COOH system (method F) or by catalytic hydrogenationin a strong acid medium (method M) or by a Clemmensen reduction in aZn/concentrated HCl medium in the presence of toluene under hotconditions (method N). This bromo ester XIX easily undergoescondensation under hot conditions in DMF with the sodium salt ofsecondary sulphonamides of general formula XX

    R--SO.sub.2 NH--R.sub.7                                    XX

in which R₇ =R₁ (except for H), or COOR₆, where R₆ =straight-chain orbranched alkyl or benzyl, to give the sulphonamide completelysubstituted on the nitrogen XXI (method I). Saponification by method Gleads to the corresponding acid XXII. The latter can be esterified underhot conditions in an alcoholic medium (R₃ OH) in the presence of astrong acid (concentrated H₂ SO₄) (method K) to give the correspondingester XXIII.

The starting intermediate IV can also be directly subjected to thecondensation reaction with the sodium salt of the compound of generalformula XX to give the corresponding sulphonamide (method I), of formulaXXIV. The latter can be saponified under the operating conditions G togive the corresponding ketosulphonamido acid XXV. In the case where R₇represents a tert.-butoxycarbonyl radical, the reaction is preceded bycleavage of the group in a hydrochloric medium in ethyl acetate (methodP) to give the ester XXV where R₁ =H, which is then saponified to theacid R₃ =H by method G. The ketone function of the compound XXIV canalso be completely or partially reduced as for the compound IX. Thepartial reduction of XXIV yields the hydroxysulphamido ester XXVI(methods C and E); this derivative is then saponified to give the acidderivative XXVII (method G), which can be esterified to compound XXVIIIin alcohol under hot conditions in a sulphuric medium (method K). Thetotal reduction of the carbonyl of XXIV to CH₂ (compound XXI) is carriedout by one of the three methods F, M and N described above. Thesulphamido ester is easily saponified by process G to the correspondingacid XXII.

2) Case where Y represents an alkoxy or benzyloxycarbonyl in IV(synthesis scheme II)

The keto-ester carbamate of general formula IVb where R₈ represents alower (C₁ to C₈) straight chain alkyl can also be partially reduced tothe hydroxy derivative or totally reduced to CH₂. The partial reductionof IVb to compound XXIX is carried out in an alcoholic solvent in thepresence of borohydride (method E). The removal of the protective groupto give the aminohydroxy acid XXX by method G must be carried out in amore concentrated basic medium and under hot conditions. Theaminohydroxy acid XXX, or its crude sodium salt, is then subjected to acondensation reaction with a sulphonyl halide of general formula VII ina basic aqueous medium, for example in sodium hydroxide at a pH ofbetween 9 and 11, to give, after acidification, the acid XXVII. ##STR9##

In a parallel manner, the reduction of the carbonyl in IV_(b) to CH₂ canbe carried out by methods F and M to give the compound XXXI, from whichthe protective groups are removed under the same conditions as for XXXto give the corresponding amino acid XXXII. This amino acid, or itssodium salt in the crude state, is subjected to a condensation reactionwith the sulphonyl halide VII according to method K to yield thecompound XXII.

3) The derivatives containing an unsaturated heterocycle --A-- areprepared from saturated esters of general formula XXI or XXIV bysubstituent bromination with the aid of N-bromosuccinimide andsimultaneous debromohydration under hot conditions in a chlorinatedsolvent such as CCl₄ for example, to give the corresponding ester XXXIII(method R), followed by saponification by method G to lead to the acidXXXIV in the furan series for example ##STR10##

4) The organic or inorganic salts of compounds of general formula Iwhere R₃ =H are prepared by a stoichiometric reaction between thecompound I (R₃ =H) and an organic or inorganic base (in the hydroxy oralcoholate form) in an alcoholic solvent or an alcohol/water mixture orin acetone. The salt is recovered by filtration (if insoluble) or byevaporation of the solvent to dryness and recrystallization ifnecessary.

EXAMPLE 1 Preparation of5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid (compound 1)

1a) Ethyl 5-bromoacetyl-2,3-dihydro-2-benzofurancarboxylate IV (Y=Br, R₂=H, A=a, R₅ =Et, n=1) (1a) Method A)

A solution of 42.5 g (0.22 mole) of ethyl2,3-dihydro-2-benzofurancarboxylate and 58.1 g (0.288 mole) ofbromoacetyl bromide in 500 ml of methylene chloride is cooled to 0° C.and then treated in the course of 15 minutes with 73.3 g (0.55 mole) ofanhydrous aluminum chloride. The mixture is stirred for a further 1 hourat 0° C. and then allowed to return slowly to 20° C. in the course of 3hours. The mixture is hydrolysed at 0° C. with concentrated hydrochloricacid in the customary manner and then extracted with methylene chlorideand the extract is washed with water and dilute sodium bicarbonate,dried and evaporated to dryness (80 g). The residue is recrystallizedfrom 250 ml of boiling isopropyl alcohol, seeding with stirring. Whencold, 56 g (yield=81%) of the intermediate of formula 1are recovered##STR11## Compound 1a

empirical formula: C₁₃ H₁₃ BrO₄

molecular weight: 313.152

broken white crystals

melting point: 70° C.

IR (KBr): √CO 1675, √COOEt 1750 cm⁻¹.

NMR (CDCl₃) δ: 1.32, t, 3H, CH₃ ; 3.40, q, 1H, ArCH₂ C(O)COOEt; 3,62, q,1H, ArCH₂ C(O)COOEt; 4.28, q, 2H, COOCH₂ Me; 4.38, s, 2H, BrCH₂ CO;5.29, q, 1H, OCHCOOEt; 6.94, d, 1H, Ar ortho OCH₂ ; 7.84 to 7.88; m, 2H,Ar ortho CO.

1b) Ethyl 5-azidoacetyl-2,3-dihydro-2-benzofurancarboxylate V (R₂ =H,n=1, A=a, R₅ =Et) (1b) (method B)

A mixture of 10 g (32 mmoles) of ethyl5-bromoacetyl-2,3-dihydro-2-benzofurancarboxylate (1a) in 130 ml ofethanol is cooled in an ice bath and then treated with a solution of 2.3g (35 mmoles) of sodium nitride in 6 ml of water, added dropwise in thecourse of 10 min. The ice bath is removed and the solution is thenstirred for 5 h at 25° C.

The expected derivative precipitates. After leaving in the refrigeratorfor 16 h, the crystals of the compound of formula 1b are recovered inthe customary way ##STR12## Compound 1b

empirical formula: C₁₃ H₁₃ N₃ O₄

molecular weight: 275.264

white crystals

melting point: 85° C.

IR (KBr): √CO 1683, √COOEt 1738, √CN₃ 2125 cm⁻¹.

NMR (CDCl₃) δ: 4.49, s, 2H, N₃ CH₂ CO.

1c) Ethyl 5-aminoacetyl-2,3-dihydro-2-benzofurancarboxylatehydrochloride VI (R₂ =H, n=1, A=a, R₅ =Et) (1c) (method C).

A solution of 9.2 g (33.4 mmoles) of ethyl5-azidoacetyl-2,3-dihydro-2-benzofurancarboxylate in 500 ml of methanoland 30 ml of N hydrochloric acid is hydrogenated in the customary mannerin the presence of 1.5 g of 10% palladium-on-charcoal under a stream ofhydrogen for 2 h 30. After purging with nitrogen, the catalyst isremoved by filtration, the filtrate is evaporated to dryness, theresidue is taken up in 100 ml of isopropyl alcohol and the mixture isstirred overnight at 25° C. The crystals consist of the compound offormula 1c and are recovered in the customary way (weight=6g-yield=63%). ##STR13## Compound 1c

empirical formula: C₁₃ H₁₆ ClNO₄

molecular weight: 285.727

white crystals

melting point: 152° C.

IR (KBr): √NH 3000, √COOEt 1740, √CO 1680 cm⁻¹.

NMR (CDCl₃) δ: 4.5 to 4.7, m, 2H, NCH₂ CO. 1d) Ethyl5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylateVIII (R=p-ClC₆ H₄ --, R₂ =H, n=1, A=a, R₅ =Et; (and for I R₁ =H andX=CO) (1d) (method D).

A suspension of 5.8 g (20.2 mmoles) of ethyl5-aminoacetyl-2,3-dihydro-2-benzofurancarboxylate hydrochloride (1c) in65 ml of pyridine cooled to -5° C. is treated with 5.5 g (26.1 mmoles)of parachlorobenzenesulphonyl chloride. The mixture is kept at thistemperature for 1/4 hour and stirring is then continued for a further 2hours after returning to 20°. The reaction mixture is hydrolysd with 100ml of water and then extracted with ethyl acetate. The organic phase iswashed twice with 100 ml of water, the pH of which has been adjusted to5.5 by the addition of concentrated HCl, and is then washed with salinewater, dried over sodium sulphate and evaporated. The residue yields twoamounts of crystals of formula 1d by dissolving in ethyl acetate andprecipitating from ether or isopropyl ether (weight=6.3 g-yield =73%)##STR14## Compound 1d

empirical formula: C₁₉ H₁₈ ClNO₆ S

molecular weight: 423.871

broken white crystals

melting point: 153° C.

IR (KBr): √SO₂ N 1160-1350, √CO 1688, √COOEt 1738, √NH 3300 cm⁻¹.

NMR (CDCl₃) δ: 4.39, d, 2H, NCH₂ CO; 5.8, t, 1H, NH; 7.42 to 7.48, dd,2H, Ar ortho of Cl; 7.78 to 7.84, dd, 2H, Ar ortho of SO₂ 1e)Saponification (method G), synthesis of5-parachlorobenzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylicacid IX (R=pCl C₆ H₄, R₂ =H, A=a; (I R₁ =H, R₃ =H, X=CO) (1)

At 25° C. a solution of 3.8 g (9 mmoles) of ethyl5-parachlorobenzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylate(1d) in 40 ml of methanol is brought to pH 11.8 by adding 10 ml of Nsodium hydroxide solution. The pH is held at 11.5 by dropwise additionof 6 ml of N sodium hydroxide solution. Stirring is continued for 1 h 30and the mixture is then cooled with ice and acidified to pH 3.3 byaddition of N hydrochloric acid. After stirring for 20 min at 0° C., thecrystals of the expected derivative are collected, rinsed with ice-waterand dried (2.7 g). By recrystallization from isopropyl alcohol, 2.05 g(yield=58%) of crystals of compound 1 are recovered, of formula##STR15## Compound 1

empirical formula: C₁₇ H₁₄ ClNO₆ S

molecular weight: 395.817

broken white crystals

melting point: 124° C.

IR (KBr): √SO₂ N 1170-1360, √CO 1695, √COOH 1730, √NH 3300 cm⁻¹.

NMR (CDCl₃) δ: 5.31, q, 1H, OCHCOO.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf=0.48

soluble in DMSO to give a 10% solution.

EXAMPLE 2 Preparation of5-(2-parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzofurancarboxylicacid (compound 2)

a) Sodium salt of N-ethoxycarbonylparachlorobenzenesulphonamide XX (R₇=EtOCO, R=p-ClC₆ H₄ ; Na salt) (2a)

A mixture formed from 85 g (0.443 mole) of parachlorobenzenesulphonamideand 157.2 g (1.13 mole) of K₂ CO₃ /KI 98/02 in 500 ml of acetone istreated at 25° C. with 62.6 g (0.576 mole) of ethyl chloroformate, addeddropwise in the course of 30 min, with mechanical stirring. The reactionis slightly exotermic and, after the temperature has stabilized at 40°C., the mixture is brought progressively to reflux for 2 hours. Aftercooling, the mixture is poured into 500 ml of crushed ice and thesulphonamide is extracted with ether. The residue obtained afterwashing, drying and evaporating to dryness is dissolved in 80 ml of hotisopropyl ether and is then precipitated by adding cyclohexane to obtain100 g (yield =86%) of white derivative of formula ##STR16##

empirical formula: C₉ H₁₀ ClNO₄ S

molecular weight: 263.70

broken white crystals

melting point: 80° C.

Twenty grams (75.8 mmoles) of the above sulphonamide are added at 25° C.to a methanolic solution of sodium methylate (prepared from 1.75 g (75.8mmoles) of sodium) while cooling in a bath of cold water and the mixtureis then stirred for 2 h 30 at 25° C. The mixture is evaporated todryness and the residue is then triturated and stirred overnight in 250ml of ether. The insoluble matter formed by compound 2a is recovered byfiltration (weight=14 g-yield=65%). ##STR17## Compound 2a

empirical formula: C₉ H₉ ClNNaO₄ S

molecular weight: 285.68

white crystals

melting point: 220° C.

b) Ethyl5-(N-ethoxycarbonylparachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylateXXIV (R=p-ClC₆ H₄ ⁻, R₇ =EtOCO, R₂ =H, n=1, A=a, R₅ =Et) (2b) (method I)

A mixture of 12.8 g (44.8 mmoles) of the above sodium salt ofN-ethoxycarbonylparachlorobenzenesulphonamide (2a) in 200 ml of DMFcooled to 4° C. in an ice bath is treated rapidly with 12.79 g (40.7mmoles) of ethyl 5-bromoacetyl-2,3-dihydrobenzofurancarboxylate preparedas in Example 1a. Stirring is then continued overnight at 25° C. andthen for 30 min in an oil bath at 50° C. After the temperature hasreturned to 25° C., the mixture is poured onto 400 ml of crushed ice andthe expected derivative is extracted with ether and recovered in thecustomary manner. 22.4 g (yield=100%) of product of formula 2b areobtained. The product can be used in the crude form or purified fromisopropyl alcohol. ##STR18## Compound 2b

empirical formula: C₂₂ H₂₂ ClNO₈ S

molecular weight: 495.934

amorphous whitish powder

melting point: 98° C.

IR (KBr): √SO₂ N 1170-1350, √CO 1700, √COOEt and NCOOEt 1755 cm⁻¹.

NMR (CDCl₃) δ: 1.12, t, 2H, NCOOCH₂ CH₃ ; 4.12, q, 2H, NCOOCH₂ CH₃ ;5.27, s, 2H, COCH₂ N; 7.51, d, 2H, Ar ortho of Cl; 8.03, d, 2H. Ar orthoof SO₂.

2c)5-(2-(N-ethoxycarbonylparachlorobenzenesulphonamido)ethyl)-2,3-dihydro-2-benzofurancarboxylateXXI (R=p-ClC₆ H₄ --, R₇ =EtOCO--, R₂ =H, A=a, R₅ =Et) (method F)

A solution of 22.4 g (40.7 mmoles) of the above crude ethyl5-(N-ethoxycarbonylparachlorobenzenesulphonamidoacetyl)-2,3-dihdyrobenzofurancarboxylate(2b) in 80 ml of CF₃ COOH is treated at 25° C. with 19.5 ml (14.19 g or122 mmoles) of triethylsilane and the mixture is stirred for 24 h. Thesolution formed is evaporated to dryness under vacuum and the residue isthen taken up in toluene and the solution is evaporated to dryness togive the compound 2c, which can be used in the crude form (yield=100%)or purified on a normal silica column eluting with a mixture of 60% ofcyclohexane, 30% of methylene chloride and 10% of ethyl acetate to givethe compound 2c in a yield of 70%, this compound having the formula##STR19## Compound 2c

empirical formula: C₂₂ H₂₄ ClNO₇ S

molecular weight: 481.951

colourless oil

IR (film): √SO₂ N 1170-1350, √COOEt and NCOOEt 1755 cm⁻¹. NMR (CDCl₃) δ:2.96, t, 2H, ArCH₂ CH₂ N; 4, t, 2H, ArCH₂ CH₂ N; 7 to 7.06, m, 2H, Arortho to CH₂.

2d) 5-(2-Parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzofurancarboxylic acid XXII (R=p-ClC₆ H₄, R₁ =R₂ =H, n=1,A=a and for I, X=CH₂, R₅ =H) (compound 2) (method G)

The above crude ethyl5-(2-(N-ethoxycarbonylparachlorobenzenesulphonamido)ethyl)-2,3-dihydro-2-benzofurancarboxylate(2c) (40.7 mmoles) is taken up in 80 ml of dioxane and the solution isthen treated with 80 ml of 5N sodium hydroxide solution and heated withstirring at 50° C. for 15 min. The mixture is poured into 500 ml of iceand extracted with ether. The aqueous phase is acidified to pH 5. Theexpected acid is extracted with ethyl acetate in the customary mannerand the residue is triturated in ether and then stirred for 1 h at 25°C. 11.45 g (yield=74%) of pulverulent white crystals of compound 2 arerecovered, this compound having the formula ##STR20## Compound 2

empirical formula: C₁₇ H₁₆ ClNO₅ S

molecular weight: 381.834

pulverulent white crystals

melting point: 153° C.

IR (KBr): √SO₂ N 1160-320, √COOH 1700, √NH 3240 cm⁻¹.

NMR (CDCl₃) δ: identical to that of compound 4.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02 Rf=0.45

soluble in DMSO to give a 10% solution.

EXAMPLE 3 Preparation of5-(2-parachlorobenzenesulphonamido-1-hydroxyethyl)-2,3-dihydro-2-benzofurancarboxylicacid (compound 3) (synthesis scheme II)

a) Ethyl 5-ethoxycarbonylaminoacetyl-2,3-dihydro-2-benzofurancarboxylateIV (Y=EtOCONH--, R₂ =H, n=1, A=a, R₅ =Et) (3a)

Using the operating method A described in Example 1 for compound 1a butreplacing bromoacetyl bromide by ethoxycarbonylaminoacetyl chlorideprepared in situ from 36.1 g (0.245 mole) of the corresponding acid andsubjecting it to a condensation reaction with 24.8 g (0.129 mole) ofethyl 2,3-dihydrobenzofurancarboxylate in the presence of 86 g (0.645mole) of aluminium chloride, 11.4 g (yield=28%) of compound 3a areobtained after purification on a silica column (C₆ H₁₂ -AcOEt-CH₂ Cl₂ :60/20/20) and recrystallization from isopropyl ether, compound 3a havingthe formula ##STR21## Compound 3a

empirical formula: C₁₆ H₁₉ NO₅

molecular weight: 321.329

broken white crystals

melting point: 82° C.

IR (KBr): √NCOOEt 1670, √CO 1700, √COOEt 1730 cm⁻¹. NMR (CDCl₃) δ: 1.24to 1.35, m, 6H, 2 CH₃ ; 3.34 to 3.68, m, 2H, OCHCH₂ ; 4.10 to 4.33, m,4H, 2 CH₂ ; 4.62, d, 2H, NCH₂ CO; 5.29, q, 1H, OCHCH₂ ; 5.7, t, 1H, NH;6.95, d, 1H, Ar ortho O; 7.84.m, 2H, Ar ortho CO.

3b) Ethyl5-(2-ethoxycarbonylamino-1-hydroxyethyl)-2-benzofurancarboxylate XXIX(R₈ =Et, R₁ =R₂ =H, n=1, A=a, R₅ =Et) (3b) (method E)

A mixture of 3.2 g (10 mmoles) of the above ethyl5-(2-ethoxycarbonylaminoacetyl)-2,3-dihydro-2-benzofurancarboxylate 3ain 30 ml of ethanol is treated at 25° C. with 0.27 g (5 mmoles) ofpotassium borohydride. After stirring for 2 h 30, 0.11 g (2 mmoles) ofsupplementary KBH₄ are added and the mixture is kept at 25° C. for afurther one hour. The reaction mixture is poured into saturated salinewater and extracted with ether and the extract is then washed with waterand with saline water and finally dried over sulphate and evaporated todryness. The residue is purified on a silica column eluting successivelywith a 90/10 hexane/ethyl acetate mixture and then a 60/20/20cyclohexane/methylene chloride/ethyl acetate mixture. The fractionscontaining the expected derivative are evaporated to dryness and thesolid obtained is then taken up in isopropyl ether. The pulverulentcrystals of the compound of formula 3b are recovered in the customarymanner (weight=1.7 g-yield= 53%) ##STR22## Compound 3b

empirical formula: C₁₆ H₂₁ NO₆

molecular weight: 323.345

broken white pulverulent crystals

melting point: 95° C.

IR (KBr): √NCOOEt 1680, √COOEt 1730-1750, √NH 3300, √OH 3370 cm⁻¹.

NMR (CDCl₃) δ: 3.15 to 3.60, m, 5H, ArCH₂ CHOAr and NCH₂ CHOH; 4.67 to4.75, m, 1H, CHOH; 6.83, d, 1H, Ar ortho of OCH₂ ; 7.10, d and 7.18 s,2H, Ar ortho CHOH.

3c) 5-(2-Amino-1-hydroxyethyl)-2,3-dihydro-2-benzofurancarboxylic acidXXX (R₁ =R₂ =H, n=1, A=a) (3c) (method G)

Using method G described in Example 2d, starting from 3 g (9.3 mmoles)of ethyl5-(2-ethoxycarbonyl-1-hydroxyethyl)-2,3-dihydro-2-benzofurancarboxylateand after heating to reflux for 1 h 30, a solution of the sodium salt ofacid XXX of formula 3c is obtained, which is not isolated ##STR23##Compound 3c

3d)5-(2-Parachlorobenzenesulphonamido-1-hydroxyethyl)-2,3-dihydro-2-benzofurancarboxylicacid XXVII (R=p-ClC₆ H₄ --, R₁ =R₂ =H, A=a and for I R₅ =H and X--CHOH)(compound 3) (method J)

The crude basic solution obtained in the above example 3c is dilutedwith crushed ice and brought to pH 11 by adding concentrated HCl and 3 g(14.2 mmoles) of parachlorobenzenesulphonyl chloride are then added. Themixture is then stirred for 4 h at 25° C., treated again with a further0.5 g (≈2.4 mmoles) of the above chloride and stirred for a further 2 h.The pH is brought to 12 by adding sodium hydroxide solution and themixture is then extracted with ether. The basic aqueous phase isacidified (HCl) to pH 7 and extracted with ethyl acetate, then acidifiedto pH 2 and extracted with ethyl acetate in the customary manner. Theresidue (2 g) obtained after evaporating off the solvent is purified ona silica (20 g) column, eluting with a 99/01 AcOEt/AcOH mixture. Thefractions containing the expected derivative are combined and evaporatedto dryness.

The residue is triturated in isopropyl ether and the insoluble matterconsisting of compound 3 is recovered in the customary manner(weight=1.6 g-yield=42%) ##STR24## Compound 3

empirical formula: C₁₇ H₁₆ ClNO₆ S

molecular weight: 397.83

pulverulent white crystals

melting point: 77° C. slow

IR (KBr): √SO₂ NH 1150-1320, √COOH 1720, √NH 3400 cm⁻¹.

NMR (CDCl₃) δ: 2.7 to 3, m, 2H, NCH₂ CHOH; 4.46 to 4.52, q, 1H, CHOH;6.49 to 6.55, q, 1H, NH; 7.30, d, 2H, Ar ortho Cl; 7.60, d, 2H, Ar orthoSO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf=0.35

soluble in DMSO to give a 10% solution.

EXAMPLE 4 Preparation of5-(2-parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzofurancarboxylicacid monohydrate (compound 4) XXXIII (R=p-ClC₆ H₄, R₁ =R₂ =H, n=1, A=aand for I X=CH₂, R₃ =H, hydrate) (synthesis scheme II)

a) Ethyl5-(2-ethoxycarbonylaminoethyl)-2,3-dihydro-2-benzofurancarboxylate XXXI(R₆ =Et, R₁ =R₂ =H, n=1, A=a, R₅ =Et) (method F).

Using the method described in Example 2c and starting from ethyl5-ethoxycarbonylaminoacetyl-2,3-dihydro-2-benzofurancarboxylate(compound 3a), the derivative of formula 4a is obtained in a yield of84% ##STR25## Compound 4a

empirical formula: C₁₆ H₂₁ NO₅

molecular weight: 307.346

white crystals

melting point: 63° C.

IR (KBr) √NCOOEt 1690, √COOEt 1735, √NH 3300 cm⁻¹.

NMR (CDCl₃) δ: 2.73, t, 2H, ArCH₂ CH₂ N; 3.37, t, 2H, ArCH₂ CH₂ N; 6.96,d, 1H, and 7.00, s, 1H, Ar ortho of CH₂ CH₂.

4b)5-(2-Parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzofurancarboxylicacid monohydrate XXXIII (methods G and J consecutively).

Starting from ethyl5-(2-ethoxycarbonylaminoethyl)-2,3-dihydro-2-benzofurancarboxylate andadapting the operating method of Example 3c according to method G, thesodium salt of the acid: ##STR26## is obtained as an intermediate, whichis not isolated but is directly subjected to a condensation reactionwith parachlorobenzenesulphonyl chloride according to method J describedin Example 3d to give, in a yield of 63%, compound 4 of formula##STR27## Compound 4

empirical formula: C₁₇ H₁₈ ClNO₆ S

molecular weight: 399.849

white crystals

melting point: 124° C.

IR (KBr): √SO₂ N 1160-1320, √COOH 1700, √NH 3240 cm⁻¹.

NMR (CDCl₃) δ: 2.4, t, 2H, ArCH₂ CH₂ --N; 2.75, q, 2H, ArCH₂ CH₂ N; 2.95to 3.3, m, 2H, ArCH₂ CHO; 4.86, q, 1H, ArCH₂ CHO; 6.45, d, 1H, Ar orthoO; 6.6, d, 1H, Ar ortho CH₂ CH₂ ; 6.65, s, 1H, Ar ortho CH₂ CH₂ and CH₂CHO; 6.91, t, 1H, NH; 7.17, d, 2H, Ar ortho Cl; 7.47, d, 2H, Ar orthoSO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 90/09/01

Rf=0.16

soluble in DMSO to give a 10% solution.

EXAMPLE 5 Preparation of5-(α-methylparachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid IX (R=p-ClC₆ H₄, R₂ =Me, n=1, A=a and for I X=CO and R₅ =H)(compound 5) (synthesis scheme I)

a) Ethyl 5-α-bromopropionyl-2,3-dihydro-2-benzofurancarboxylate IV(Y=Br, R₂ =Me, n=1, A=a, R₅ =Et). Adapting the operating method Adescribed in Example 1a to α-bromopropionyl bromide, compound 5a isobtained in a yield of 72%, this compound having the formula ##STR28##Compound 5a

empirical formula: C₁₄ H₁₅ BrO₄

molecular weight: 327.179

white crystals

melting point: 97° C.

IR (KBr): √CO 1680, √COOEt 1760 cm⁻¹.

NMR (CDCl₃) δ: 1.32, t, 3H, CH₂ CH₃ ; 1.88, d, 3H, CHCH₃ ; 3.35 to 3.68,m, 2H, OCHCH₂ ; 4.28, q, 2H, CH₂ CH₃ ; 5.19 to 5.34, m, 2H, CHCH₃ andOCHCH₂ ; 6.95, d, 1H, Ar ortho O; 7.89 to 7.92, m, 2H, Ar ortho CO.

b) Ethyl 5-(α-azidopropionyl)-2,3-dihydro-2-benzofurancarboxylate V (R₂=Me, n=1, A=a, R₅ =Et). Using the operating method used to preparecompound 1b, starting from ethyl5-(α-bromopropionyl)-2,3-dihydro-2-benzofurancarboxylate, compound 5b isobtained in a yield of 100%, this compound having the formula ##STR29##Compound 5b

empirical formula: C₁₄ H₁₅ N₃ O₄

molecular weight: 289.291

colourless oil.

c) Ethyl 5-(α-aminopropionyl)-2,3-dihydrobenzofurancarboxylatehydrochloride VI (R₂ =Me, n=1, A=a, R₅ =Et) (5c)

Adaptation of operating method C (cf. Example 1c) to ethyl5-(α-azidopropionyl)-2,3-dihydro-2-benzofurancarboxylate (5b) enablescompound 5c to be prepared in a yield of 61.4%, this compound having theformula ##STR30## Compound 5c

empirical formula: C₁₄ H₁₈ ClNO₄

molecular weight: 299.754

white crystals.

d) Ethyl5-(α-methylparachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylateVIII (R=p-ClC₆ H₄ --, R₂ =Me, n=1, A=a, R₅ =Et) (5d).

Adapting operating method D (cf. Example 1d) to ethyl5-(α-aminopropionyl)-2,3-dihydro-2-benzofurancarboxylate hydrochloride,compound 5d is obtained in a yield of 45%, this compound having theformula ##STR31## Compound 5d

empirical formula: C₂₀ H₂₀ ClNO₆ S

molecular weight: 437.898

broken white crystals

melting point: 137° C.

IR (KBr): √SO₂ N 1170-1355, √CO 1670, √COOEt 1755, √NH 3280 cm⁻¹.

5e)5-(α-Methylparachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid (compound 5).

Using operating method G (cf. Example 1e) to saponify ethyl5-(α-methylparachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylate,compound 5 is obtained in a yield of 63%, this compound having theformula ##STR32## Compound 5

empirical formula: C₁₈ H₁₆ ClNO₆ S

molecular weight: 409.844

white crystals

melting point: 134°-136° C.

IR (KBr): √SO₂ N 1175-1355, √CO 1670, √COOH 1730, √NH 3290 cm⁻¹.

NMR (CDCl₃) δ: 1.37, d, 3H, CH₃ ; 3.33 to 3.70, m, 2H, CH₂ CHO; 4.84, m,1H, CHCH₃ ; 5.27, q, 1H, CH₂ CHO; 6.1, d, 1H, NH; 6.9, d, 1H, Ar orthoO; 7.33, d, 2H, Ar ortho Cl; 7.62 to 7.8, m, 4H, Ar ortho SO₂ and Arortho CO.

TLC: silica gel 60 Merck F 254 eluant: chloroform/methanol/acetic acid:80/18/02 Rf=0.49

soluble in DMSO to give a 10% solution.

EXAMPLE 65-(2-Parachlorobenzenesulphonamido-1-hydroxypropyl)-2,3-dihydro-2-benzofurancarboxylicacid XIV (R=p-Cl--C₆ H₄ --, R₂ =Me, n=1, A=a, and for I R₁ =R₃ =H, andX=CHOH) (scheme I) (compound 6)

a) Ethyl 5-(2-amino-1-hydroxypropyl)-2,3-dihydro-2-benzofurancarboxylate XII (R₂ =Me, n=1, A=a, R₅ =Et) (6a). Startingfrom 21 mmoles of ethyl5-(α-azidopropionyl)-2,3-dihydro-2-benzofurancarboxylate alreadydescribed in Example 5b and using method C but hydrogenating for a muchlonger period, 2.5 g (yield=45%) of compound 6a are obtained afterpurification on a silica column and eluting with a 90/09/01chloroform/methanol/ammonia mixture, compound 6a having the formula##STR33## Compound 6a

empirical formula: C₁₄ H₁₉ NO₄

molecular weight: 265.31

broken white crystals

melting point: 115° C.

IR (KBr): √COOEt 1730, √NH and OH 3280-3340 cm⁻¹.

NMR (CDCl₃) δ: 0.86, d, 3H, CH₃ CH; 1.19, t, 3H, CH₃ CH₂ ; 2.95, m, 1H,CHCH₃ ; 3.15 to 3.50, m, 2H, ArCH₂ CHO; 3.68, s, 1H, OH; 4.13, q, 2H,CH₃ CH₂ ; 4.26, d, 1H, CHOH; 5.03 to 5.15, m, 1H, ArCH₂ CHO; 6.70, d,1H, Ar ortho O; 6.95, d, 1H and 7.07, s, 1H, Ar ortho CHOH.

b) Ethyl5-(2-parachlorobenzenesulphonamido-1-hydroxypropyl)-2,3-dihydro-2-benzofurancarboxylateXIII (R=p-Cl--C₆ H₄, R₂ =Me, n=1, R₅ =Et) (compound 6b).

Using the above ethyl5-(2-amino-1-hydroxypropyl)-2,3-dihydro-2-benzofurancarboxylate as thestarting material and adapting method D already described in Example 1c,compound 6b is obtained in a yield of 73%, this compound having theformula ##STR34## Compound 6b

empirical formula: C₂₀ H₂₂ ClNO₆ S

molecular weight: 439.91

c)5-(2-Parachlorobenzenesulphonamido-1-hydroxypropyl)-2,3-dihydro-2-benzofurancarboxylicacid (compound 6).

Starting from the above compound 6b (3.3 mmoles) and using method G (cf.Example 1d), compound 6 is obtained in a yield of 44%, this compoundhaving the formula ##STR35## Compound 6

empirical formula: C₁₈ H₁₈ ClNO₆ S

molecular weight: 411.86

white crystals

melting point: 185° C.

IR (KBr): √SO₂ N 1170-1335, √COOH 1710-1735, √NH 3350, √OH 3490 cm⁻¹.

NMR (CDCl₃) δ: 0.79, d, 3H, CH₃ ; 4.5, d, 1H, CHOH; 6.43, d, 1H, NH;7.35, d, 2H, Ar ortho Cl; 7.65, d, 2H, ortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf=0.34

soluble in DMSO to give a 5% solution.

EXAMPLE 7 6-(2-Parachlorobenzenesulphonoamidoethyl)-2-chromancarboxylicacid I (R=p-ClC₆ H₄ --, R₁ =R₂ =R₃ =H, n=1, A=g, X=CH₂) (compound 7)(scheme I)

a) Ethyl 6-bromoacetyl-2-chromancarboxylate IV (Y=Br, R₂ =H, n=1, A=g,R₅ =Et) (compound 7a).

Using method A according to Example 1a and applying it to 42 mmoles ofethyl 2-chromancarboxylate, compound 7a is obtained in a yield of 83%,this compound having the formula ##STR36## Compound 7a

empirical formula: C₁₄ H₁₅ BrO₄

molecular weight: 327.18

pulverulent white crystals

melting point: 89° C.

IR (KBr): √CO 1690, √COOEt 1755 cm⁻¹.

NMR (CDCl₃) δ: 1.28, t, 3H, CH₃ ; 2.15 to 2.30, m, 2H, OCHCH₂ ; 2.7 to2.9, m, 2H, OCHCH₂ CH₂ ; 4.25, q, 2H, CH₂ CH₃ ; 4.38, s, 2H, Br CH₂ ;4.82, t, 1H, OCH; 6.98, d, 1H, Ar ortho O; 7.73 to 7.79, m, 2H, Ar orthoCO.

7b) Ethyl6-(N-ethoxycarbonylparachlorobenzenesulphonamido)acetyl-2-chromancarboxylateXXIV (R=p-ClC₆ H₄ --, R₇ =EtOCO--, R₂ =H, n=1, A=g, R₅ =Et) (compound7b)

Using method I described in Example 2a and 2b and adapting it to theabove compound 7a, compound 7b is obtained in a yield of 91%, thiscompound having the formula ##STR37## Compound 7b

empirical formula: C₂₃ H₂₄ ClNO₈ S

molecular weight: 509.96

pulverulent white crystals

melting point: 131° C.

IR (KBr): √SO₂ N 1170-1330, √CO 1690, √COOEt and NCOOEt 1745 cm⁻¹.

NMR (CDCl₃) δ: 1.12, t, 3H, NCOOCH₂ CH₃ ; 4.11, q, 2H, NCOOCH₂ CH₃ ;5.28, s, 2H, NCH₂ CO; 7.51, d, 2H, Ar ortho Cl; 8.02, d, 2H, Ar orthoSO₂.

7c) 6-(2-Parachlorobenzenesulphonamidoethyl)-2-chromancarboxylic acid(compound 7) XXII (R=p-ClC₆ H₄ --, R₁ =R₂ =H, n=1, A=g, and for I R₃ =H,X=CH₂).

Adaptation of operating method F described in Example 2c to 9.8 mmolesof ethyl6-[(N-ethoxycarbonylparachlorobenzenesulphonamido)acetyl]-2-chromancarboxylateenables the compound of formula 7c to be prepared in a quantitativeyield, which compound is saponified in the crude form withoutpurification ##STR38## Compound 7c

Compound 7c is treated directly by method G described in Example 2d togive compound 7 in a yield of 35% after recrystallization from ethanol,compound 7 having the formula ##STR39## Compound 7

empirical formula: C₁₈ H₁₈ ClNO₅ S

molecular weight: 395.86

white crystals

melting point: 142° C.

IR (KBr): √SO₂ NH 1165-1325, √COOH 1720, √NH 3300 cm⁻¹.

NMR (CDCl₃) δ: 2.08 to 2.35, m, 2H, OCHCH₂ CH₂ ; 2.63 to 2.78, m, 4H,OCHCH₂ CH₂ and ArCH₂ CH₂ N; 3.14, t, 2H, ArCH₂ CH₂ N; 4.68, q, 1H, O CH;6.74 to 6.86, m, 3H, Ar ortho O and ortho CH₂ ; 7.45, d, 2H, Ar orthoCl; 7.72, d, 2H, Ar ortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf: 0.67

soluble in DMSO to give a 20% solution.

EXAMPLE 85-(2-Parachlorobenzenesulphonamidoethyl)-1,3-benzodioxole-2-carboxylicacid I (R₁ =R₂ =R₃ =H, n=1, A=c, X=CH₂) (scheme I) (compound 8)

8a) Ethyl 5-bromoacetyl-1,3-benzodioxole-2-carboxylate IV (R₂ =H, n=1,A=c, R₅ =Et)

Using operating method A described in Example 1a but starting from ethyl1,3-benzodioxole-2-carboxylate (20.6 mmoles), compound 8a is obtained ina yield of 60%, this compound having the formula ##STR40## Compound 8a

empirical formula: C₁₂ H₁₁ BrO₅

molecular weight: 315.124

white crystals

melting point: 50°-51° C.

IR (KBr): √CO 1685, √COOEt 1760 cm⁻¹.

NMR (CDCl₃) δ: 1.34, t, 3H, CH₃ ; 4.32, q, 2H, OCH₂ ; 4.37, s, 2H, BrCH₂; 6.40, s, 1H, CH; 6.94, d, 2H, Ar ortho O; 7.51, d, 1H and 7.63, dd,1H, Ar ortho CO.

8b) Ethyl5-[(N-ethoxycarbonylparachlorobenzenesulphonamido)acetyl]-1,3-benzodioxole-2-carboxylateXXIV (R=p-ClC₆ H₄ --, R₇ --COOEt, R₂ =H, n=1, A=c, R₅ =Et) (compound8b).

Adaptation of method I described in Example 2b to 11 mmoles of ethyl5-bromoacetyl-1,3-benzodioxole-2-carboxylate enables compound 8b to beprepared in a quantitative yield, this compound having the formula##STR41## Compound 8b

empirical formula: C₂₁ H₂₀ ClNO₉ S

molecular weight: 497.906

colourless foam

NMR (CDCl₃) δ: 1.13, t, 3H, CH₃ CH₂ OCON; 4.12, q, 2H, CH₃ CH₂ OCON;5.26, s, 2H, CH₂ N; 7.52, d, 2H, Ar ortho Cl; 8.02, d, 2H, Ar ortho SO₂.

8c) 5-(Parachlorobenzenesulphonamidoethyl)-1,3-benzodioxole-2-carboxylicacid (compound 8).

Applying method F described in Example 2c to 11 mmoles of the abovederivative 8b, the intermediate 8c is obtained in a quantitative yield,this intermediate having the formula ##STR42## Compound 8c

This derivative is not purified and is used in the crude form to give,by saponification according to method G (cf. Example 2d) andpurification in isopropyl ether, compound 8 in a yield of 68%, thiscompound having the formula ##STR43## Compound 8

empirical formula: C₁₆ H₁₄ ClNO₆ S

molecular weight: 383.806

white crystals

melting point: 138° C.

IR (KBr): √SO₂ N 1165-1330, √COOH 1730, √NH 3295 cm⁻¹.

NMR (CDCl₃) δ: 2.65, t, 2H, ArCH₂ CH₂ N; 3.07, t, 2H, ArCH₂ CH₂ N; 6.24,s, 1H, CH; 6.52 to 6.59, m, 2H, Ar ortho O; 6.71, d, 1H, Ar ortho CH₂ ;7.42, d, 2H, Ar ortho Cl; 7.70, d, 2H, Ar ortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf: 0.34

soluble in DMSO to give a 20% solution.

EXAMPLE 9 Preparation of5-(2-parachlorobenzenesulphonamidoethyl)-2-indanecarboxylic acid I (R₁=R₂ =R₃ =H, n=1, X=CH₂, A=f) (compound 9) (synthesis scheme I)

a) Methyl 5-bromoacetyl-2-indanecarboxylate.

Using method A described in Example 1a, starting from 17 mmoles of ethyl2-indanecarboxylate and after purification from isopropyl ether,compound 9a is obtained in a yield of 80%, this compound having theformula ##STR44## Compound 9a

empirical formula: C₁₃ H₁₃ BrO₃

molecular weight: 297.153

white crystals

melting point: 91° C.

IR (KBr): √CO 1690, √COOEt 1730 cm⁻¹.

NMR (CDCl₃) δ: 3.27 to 3.41, m, 5H, CH₂ CHCH₂ ; 3.74, s, 3H, CH₃ O;4.43, s, 2H, BrCH₂ CO; 7.32, d, 1H, Ar meta CO; 7.78 to 7.83, m, 2H, Arortho CO.

b) Ethyl5-[(N-ethoxycarbonylparachlorobenzenesulphonamido)acetyl]-2-indanecarboxylateXXIV (R=p-ClC₆ H₄, R₇ =EtOCO, n=1, A=f, R₅ =Et) (compound 9b).

Applying method I described in Example 2b to 13 mmoles of ethyl5-bromoacetyl-2-indanecarboxylate, compound 9b is obtained in a yield of94%, this compound having the formula ##STR45## Compound 9b

empirical formula: C₂₂ H₂₂ ClNO₇ S

molecular weight: 479.935

white crystals

melting point: 45° C.

IR (KBr): √SO₂ N 1185-1330, √CO 1700, √COOEt and NCOOEt 1740 cm⁻¹.

NMR (CDCl₃) δ: 1.12, t, 3H, CH₃ CH₂ ; 4.13, q, 2H, CH₃ CH₂ ; 5.32, s,2H, NCH₂ CO; 7.52, d, 2H, Ar ortho Cl; 8.03, d, 2H, Ar ortho SO₂.

9c) 5-(2-Parachlorobenzenesulphonamidoethyl)-2-indanecarboxylic acid(compound 9)

Applying method F described in Example 2c to 12 mmoles of the abovederivative 9b, the intermediate 9c is obtained in a quantitative yield,this intermediate having the formula ##STR46## Compound 9c

This derivative is not purified and is used in the crude form to give,after saponification by method G (Example 2d) and after purificationfrom isopropyl ether, compound 9 in a yield of 63%, this compound havingthe formula ##STR47## Compound 9

empirical formula: C₁₈ H₁₈ ClNO₄ S

molecular weight: 379.862

white crystals

melting point: 140° C.

IR (KBr): √SO₂ N 1158-1320, √COOH 1695, √NH 3250 cm⁻¹.

NMR (CDCl₃): 2.7, t, 2H, ArCH₂ CH₂ N; 3.03 to 3.32, m, 7H, ArCH₂ CH₂ Nand CH₂ CHCH₂ ; 6.82 to 6.89, m, 2H, Ar ortho CH₂ CH₂ N; 7.05, d, 1H, Armeta CH₂ CH₂ N; 7.4, d, 2H, Ar ortho Cl; 7.7, d, 2H, Ar ortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 90/09/01

Rf: 0.40

soluble in DMSO to give a 10% solution.

EXAMPLE 105-(2-Parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzothiophenecarboxylicacid I (R₁ =R₂ =R₃ =H, n=1, A=d, X=CH₂) (compound 10) (synthesis schemeI)

a) Ethyl 5-bromoacetyl-2,3-dihydro-2-benzothiophenecarboxylate IVa(Y=Br, R₂ =H, n=1, A=d, R₅ =Et) (10a).

Using method A according to Example 1a and applying it to 31 mmoles ofethyl 2,3-dihydro-2-benzothiophenecarboxylate and after crystallizationfrom isopropyl ether, compound 10a is obtained in a yield of 81%, thiscompound having the formula: ##STR48## Compound 10a

empirical formula: C₁₃ H₁₃ BrO₃ S

molecular weight: 329.217

broken white crystals

melting point: 78° C.

IR (KBr): √CO 1680, √COOEt 1730 cm⁻¹.

NMR (CDCl₃): 1.28, t, 3H, CH₃ ; 3.45 to 3.81, m, 2H, SCHCH₂ ; 4.2, q,2H, OCH₂ ; 4.38, s, 2H, BrCH₂ ; 4.49, q, 1H, OCHCH₂ ; 7.24, d, 1H, Arortho S; 7.73 to 7.80, m, 2H, Ar ortho CO.

10b) Ethyl5-(N-ethoxycarbonylparachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzothiophenecarboxylateXXIV (R=p-C₆ H₄ --, R₇ =EtOCO, R₂ H, n=1, A=d, R₅ =Et) (compound 7b)

Using method I described in Example 2a and 2b and adapting it to 12mmoles of the above compound 10a, compound 10b is obtained in a yield of95% after purification on a silica column and eluting with a 60/20/20cyclohexane/dichloromethane/acetic acid mixture; this compound is usedwithout further purification and has the formula ##STR49## Compound 10b

empirical formula: C₂₂ H₂₂ ClNO₇ S₂

molecular weight: 512.00

yellow viscous oil

IR (film): √SO₂ N 1160-1340, √CO 1695, √COOEt 1730, √NCOOEt 1750 cm⁻¹.

NMR (CDCl₃): 1.12, t, 3H, NCOOCH₂ CH₃ ; 4.12, q, 2H, NCOOCH₂ CH₃ ; 5.28,s, 2H, NCH₂ CO; 7.52, dd, 2H, Ar ortho Cl; 8.02, dd, 2H, Ar ortho SO₂.

10c)5-(2-Parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzothiophenecarboxylicacid XXII (R=p-Cl--C₆ H₄ --, R₁ =R₂ =H, n=1, A=d and for I R₃ =H andX=CH₂) (compound 7)

Adaption of operating method F described in Example 2c to 10.5 mmoles ofethyl5-[(N-ethoxycarbonylparachlorobenzenesulphonamido)acetyl]-2,3-dihydro-2-benzothiophenecarboxylateenables the compound of formula 10c to be prepared in a quantitativeyield; this compound is not purified ##STR50## Compound 10c

This derivative is saponified directly by method G described in Example2d to give compound 10 in a yield of 60% after recrystallization fromisopropyl alcohol, compound 10 having the formula ##STR51## Compound 10

empirical formula: C₁₇ H₁₆ ClNO₄ S₂

molecular weight: 397.899

bright yellow crystals

melting point: 152° C.

IR (KBr): √SO₂ N 1175-1340, √COOH 1720, √NH 3290 cm⁻¹.

NMR (CDCl₃) δ: 2.63, t, 2H, ArCH₂ CH₂ N; 3.03, t, 2H, ArCH₂ CH₂ N; 3.25to 3.6, m, 2H, SCHCH₂ ; 4.36, q, 1H, SCHCH₂ ; 6.77 to 6.98, m, 3H, Arortho CH₂ and S; 7.37, d, 2H, Ar ortho Cl; 7.67, d, 2H, Ar ortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf: 0.62

soluble in DMSO to give a 20% solution.

EXAMPLE 11 5-(Parachlorobenzenesulphonamidoethyl)-2-benzofurancarboxylicacid XXXI (R=p-ClC₆ H₄ --, R₁ =R₂ =H, n=1, A=b, and for I R₃ =H andX=CH₂) (compound 11) (synthesis scheme III)

a) Ethyl5-(2-parachlorobenzenesulphonamidoethyl)-2-benzofurancarboxylate XXXIII(R=p-ClC₆ H₄ --, R₁ =R₂ =H, n=1, A=a) (compound 11a) (method R)

A mixture of 1 g (2.08 mmoles) of ethyl [2-(N-ethoxycarbonylparachlorobenzenesulphonamido)ethyl]-2,3-dihydro-2-benzofurancarboxylate(cf. Example 2c) and 0.41 g (2.28 mmoles) of N-bromosuccinimide in 10 mlof CCl₄ is stirred overnight at 25° C. and then heated on an oil bath at45° C. The orange insoluble matter (succinimide) is filtered off on aglass frit, rinsed with a little CCl₄ and removed. The organic phase isevaporated to dryness in a rotary evaporator under vacuum to givecompound 11a in a quantitative yield; this compound is not purified##STR52## Compound 11a

empirical formula: C₂₂ H₂₂ ClNO₇ S

molecular weight: 479.935

viscous amber oil

NMR (CDCl₃) δ: 1.17, t, 3H, NCOOCH₂ CH₃ ; 1.44, t, 3H, COOCH₂ CH₃ ;3.14, t, 2H, ArCH₂ CH₂ N; 4.04 to 4.16, m, 4H, ArCH₂ CH₂ N and NCOOCH₂CH₃ ; 4.44, q, 2H, COOCH₂ CH₃ ; 7.27 to 7.60, m, 6H, OCCH, Ar ortho O,CH₂ and Cl; 7.80, d, 2H, Ar ortho SO₂.

b) 5-(2-Parachlorobenzenesulphonamidoethyl)-2-benzofurancarboxylic acid(compound 11) (method G)

The above crude derivative 11a is dissolved in 4 ml of dioxane and thesolution is then diluted with 2 ml of water and treated with 2.1 ml of10N sodium hydroxide solution and stirred for 2.5 h at 50° C. and themixture is treated as described in Example 2d and then purified on asilica (7 g) column eluting with a 950/045/005chloroform/methanol/acetic acid mixture.

The fractions containing the expected derivative are combined andevaporated to dryness. The residue is recrystallized from isopropanol togive 300 mg (yield=40%) of compound 11 of formula: ##STR53## Compound 11

empirical formula: C₁₇ H₁₄ ClNO₅ S

molecular weight: 379.818

white crystals

melting point: 195° C.

IR (KBr): √SO₂ N 1180-1345, √COOH 1695, √NH 3350 cm⁻¹.

NMR (CDCl₃) δ: 2.82, t, 2H, ArCH₂ CH₂ N; 3.13, t, 2H, ArCH₂ CH₂ N; 7.13,d, 1H, Ar ortho O; 7.27 to 7.43, m, 5H, Ar ortho CH₂, Cl and OCCH; 7.66,d, 2H, Ar ortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf: 0.47

Soluble in DMSO to give a 5% solution.

EXAMPLE 125-(2-Parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzofurancarboxylicacid XXII (R₁ =R₂ =H, R=p-Cl--C₆ H₄, A=a, n=1, and for I R₃ H, X=CH₂((compound 2)

12a) Ethyl 5-(2-bromoethyl)-2,3-dihydro-2-benzofurancarboxylate XIX (R₂=H, R₅ =Et, A=a, n=1)

A solution of 3 g (9.6 mmoles) of ethyl5-bromoacetyl-2,3-dihydro-2-benzofurancarboxylate (cf. Example 1a) in 22ml of trifluoroacetic acid is cooled in an ice bath and then treatedwith 2.45 g (21 mmoles) of triethylsilane added dropwise, at atemperature of between 0° C. and +5° C., and is then allowed to returnslowly to normal temperature overnight. The reaction mixture ishydrolysed in 200 ml of crushed ice and extracted with ether. Theorganic phase is washed with water and with saline water and then driedover sulphate and evaporated to dryness. The two-phase residue (compound12a+silanols) is rectified under vacuum to give, after the silylproducts have passed over at the top, a fraction containing 2.44 g(yield=85%) of pure compound 12a of formula ##STR54## Compound 12a

empirical formula: C₁₃ H₁₅ BrO₃

molecular weight: 299.17

colourless oil

boiling point: 160° C. under 10⁻³ mbars

IR (KBr): √COOEt 1760 cm⁻¹.

NMR (CDCl₃): 1.32, t, 3H, CH₃ ; 3.09, t, 2H, ArCH₂ CH₂ Br; 3.30 to 3.62,m, 2H, ArCH₂ CHO; 3.52, t, 2H, ArCH₂ CH₂ Br; 4.27, q, 2H, OCH₂ ; 5.2, q,1H, ArCH₂ CHO; 6.84, d, 1H, Ar ortho O; 6.97 to 7.03, m, 2H, Ar orthoCH₂.

12b) Ethyl5-(2-(N-ethoxycarbonylparachlorobenzenesulphonamido)ethyl)-2,3-dihydro-2-benzofurancarboxylateXXI (R=p-Cl--C₆ H₄, R₇ =COOEt, R₂ =H, n=1, A=a) (compound 2c).

Using method I described in Example 2 to prepare the intermediate 2b andstarting from 1.5 g (5 mmoles) of ethyl5-(2-bromoethyl)-2,3-dihydro-2-benzofurancarboxylate (compound 12a),compound 2c is obtained in a quantitative yield, this compound havingthe formula: ##STR55## Compound 2c

The characteristics of this compound have already been reported inExample 2 and it is used in the crude state in the following step. Thesaponification is carried out as in Example 2 to give compound 2 alreadydescribed and having the same physicochemical properties.

EXAMPLE 13 Preparation of5-(2-parachlorobenzenesulphonamido-1-hydroxyaminoethyl)-2,3-dihydro-2-benzofurancarboxylicacid XI (R=p-Cl--C₆ H₄, R₂ =H, R₄ =H, A=a, n=1, and for I R₁ =R₃ =H,X=C=N--OR₄) (compound 13) (method H) (synthesis scheme I)

A solution of 1 g (2.5 mmoles) of5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid (cf. Example 1) in 10 ml of pyridine is treated with 0.26 g (2.75mmoles) of hydroxylamine hydrochloride and stirred for 20 h at 25° C.The mixture is evaporated to dryness under vacuum, the residue is takenup in toluene, the solution is again evaporated and the residue is thendissolved in ethyl acetate and the solution is washed with water andwith a dilute citric acid solution and then treated with a dilutesolution of sodium bicarbonate so as to obtain a final pH of 5 andfinally is washed with a solution of saline water. The organic phase isdried over sulphate and evaporated to dryness and the residue istriturated in isopropyl ether to give 700 mg (yield=68%) of compound 13of formula: ##STR56## Compound 13

empirical formula: C₁₇ H₁₅ ClN₂ O₆ S

molecular weight: 410.832

light yellow amorphous powder

melting point slow from 90° C.

IR (KBr): √SO₂ NH 1170-1335, √C=N 1595, √COOH 1730, √NH 3300 cm⁻¹.

NMR (CDCl₃) δ: 3.74 and 3.93, 2s, 2H, NCH₂ ; 7.49 and 7.63, 2d, 2H, Arortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf: 0.32

soluble in DMSO to give a 10% solution.

EXAMPLE 14 Preparation of5-(2-parachlorobenzenesulphonamido-1-methoxyiminoethyl)-2,3-dihydro-2-benzofurancarboxylicacid XI (R=p-Cl--C₆ H₄, R₂ =H, R₄ =Me, A=a, n=1, and for I R₁ =R₃ =H,X=C=N=OR₄) (compound 14) (synthesis scheme I)

Using the same method as that described in Example 13 on an identicalmolar fraction but starting from O-methylhydroxylamine hydrochloride(310 mg; 3.8 mmoles), compound 14 is obtained in a yield of 66%, thiscompound having the formula: ##STR57## Compound 14

empirical formula: C₁₈ H₁₇ ClN₂ O₆ S

molecular weight: 424.859

bright yellow amorphous powder

melting point slow from 64° C.

IR (KBr): √SO₂ NH 1170-1340; √C=N 1590; √COOH 1740; √NH 3300 cm⁻¹.

NMR (CDCl₃) δ: 3.70 and 3.90, 2s, 3H, OCH₃ ; 4 and 4.12, 2d, 2H, N CH₂ ;5.56 and 5.67, 2t, 1H, NH.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf: 0.48

soluble in DMSO to give a 10% solution.

EXAMPLE 15 Preparation of ethyl5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylateVIII (R=p-Cl--C₆ H₄, R₂ =H, R₅ =Et, A=a, n=1, and for I R₁ =H, R₃ =Et,X=CO) (compound 1d) (method K) (synthesis scheme I)

A mixture of 3.95 g (10 mmoles) of5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid (cf. Example 1) in 30 ml of anhydrous ethanol and containing 0.2 mlof concentrated sulphuric acid is heated under reflux for 2 hours andthen, after the temperature has returned to 25° C., the mixture isevaporated to dryness in a rotary evaporator under vacuum. The residueis taken up in ethyl acetate and the solution is washed with water andwith a dilute solution of sodium bicarbonate and then with water andwith saline water. The organic phase is dried over sodium sulphate andevaporated to dryness and the residue is triturated in isopropyl etherto give compound 1d in a yield of 85%, this compound having the formula:##STR58## Compound 1d

The physicochemical characteristics of this compound have already beenreported in Example 1.

EXAMPLE 16 Preparation of5-(N-methylparatoluenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid XXV (R=p-Me-C₆ H₄, R₇ =Me, R₂ =H, A=a, n=1, and for I R₁ =Me, X=CO)(compound 16)

a) Ethyl5-(N-methylparatoluenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylate(16a). Using method I described in Example 2b but applying it to thesodium salt of N-methylparatoluenesulphonamide (1 g; 5.4 mmoles) andsubjecting it to a condensation reaction with 1.7 g (5.4 mmoles) ofethyl 5-bromoacetyl-2,3-dihydro-2-benzofurancarboxylate, compound 16a isobtained in a quantitative yield, this compound having the formula##STR59## Compound 16a

empirical formula: C₂₀ H₂₃ NO₆ S

molecular weight: 405.461

whitish foam which is not isolated.

b) Saponification of compound 16a to derivative 16 (method G). The abovecrude ester 16a is saponified by method G described in Example 1e togive 1.1 g (yield=52%) of compound 16 after purification on a silica (20g) column and elution with a 950/045/005 chloroform/methanol/acetic acidmixture, compound 16 having the formula ##STR60## Compound 16

empirical formula: C₁₉ H₁₉ NO₆ S

molecular weight: 389.426

white crystals

melting point: 149° C.

IR (KBr): √SO₂ N 1160-1335, √CO 1680, √COOH 1740 cm⁻¹.

NMR (CDCl₃) δ: 2.39, s, 3H, MeN; 2.74, s, 3H, MeAr; 3.30 to 3.63, m, 2H,OCHCH₂ ; 4.4, s, 2H, NCH₂ CO; 5.22, q, 1H, OCHCH₂ ; 6.87, d, 1H, Arortho O; 7.28, d, 2H, Ar ortho CH₃ ; 7.65, d, 2H, Ar ortho SO₂ ; 7.8, m,2H, Ar ortho CO.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic

acid: 80/18/02

Rf: 0.56

soluble in DMSO to give a 10% solution.

EXAMPLE 17 Sodium5-(2-parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzofurancarboxylateI (R=p-Cl--C₆ H₄, R₁ =R₂ =H, R₃ =Na, n=1, X=CH₂, A=a) (compound 17)

A mixture of 1 g (2.6 mmoles) of5-(2-parachlorobenzenesulphonamidoethyl)-2,3-dihydro-2-benzofurancarboxylicacid (compound 2, Example 2) in 10 ml of RP ethanol is cooled in an icebath and then treated with a stoichiometric amount (+10% excess) of asolution of sodium methylate, added dropwise. After stirring for 15 min,the mixture is brought to 50° C. on an oil bath for 15 min, and afterleaving to stand overnight, the insoluble sodium salt is filtered off togive compound 17 in a yield of 80%, this compound having the formula##STR61## Compound 17

empirical formula: C₁₇ H₁₅ ClNNaO₅ S

molecular weight: 403.816

white crystals

melting point: >280° C.

IR (KBr): √COONa 1620 cm⁻¹.

soluble in water to give a 1.5% solution.

EXAMPLE 185-(Parachlorobenzenesulphonamidoacetyl)-2,3-dihydrobenzofurancarboxylicacid XXV (R=p-Cl--C₆ H₄, R₁ =R₂ =H, n=1, A=a and for I X=CO, R₃ =4)(compound 1) (method P, synthesis scheme I).

a) Sodium salt of N-tert.-butoxycarbonyl-parachlorobenzenesulphonamideXX (R=p-Cl--C₆ H₄, R₇ =t-BuOCO, Na salt), compound 18a.

Using the operating method described in Example 2a but subjecting 11.4 g(52 mmoles) of di-tert.-butylpyrocarbonate to a condensation reactionwith 5 g (26 mmoles) of parachlorobenzenesulphonamide, the compound offormula ##STR62## is obtained in a yield of 70% after purifiction fromcyclohexane.

empirical formula: C₁₁ H₁₄ ClNO₄ S

molecular weight: 291.753

white crystals

melting point: 128° C.

IR (KBr): √SO₂ N 1170-1345; √COO 1740; √NH 3270 cm⁻¹.

The sodium salt of this compound is prepared starting from 2 g (6.9mmoles) of the above compound using operating method 2a to give compound18a in a yield of 85%, this compound having the formula ##STR63##Compound 18a

empirical formula: C₁₁ H₁₃ ClNNaO₄ S

molecular weight: 313.746

white crystals

instantaneous melting point 210°-215° C. with decomposition

IR (KBr): √NCOO 1640 cm⁻¹.

18b) Ethyl5-(N-tert.-butoxycarbonyl-parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylateXXIV (R=p-Cl--C₆ H₄, R₇ =COOtBu, R₂ =H, n=1, A=a, R₅ =Et) (compound 18b)

Starting from 1 g (3.2 mmoles) of the sodium salt ofN-tert.-butoxycarbonyl-parachlorobenzenesulphonamide and subjecting thisto a condensation reaction with 0.90 g (2.85 mmoles) of ethyl5-bromoacetyl-2,3-dihydro-2-benzofurancarboxylate (compound 1a) inaccordance with the process described in Example 2b, crude compound 18bis obtained in a yield of 90%, this compound having the formula:##STR64## Compound 18b

empirical formula: C₂₄ H₂₆ ClNO₈ S

molecular weight: 523.99

viscous amber oil

NMR (CDCl₃) δ: 1.3, s, 9H, (CH₃)₃ C; 3.36, t, 3H, CH₃ CH₂ ; 3.44 to3.63, m, 2H, OCHCH₂ ; 4.3, q, 2H, CH₂ CH₃ ; 5.24, s, 2H, NCH₂ ; 5.31, q,1H, OCH; 6.98, d, 1H, Ar ortho O; 7.52, d, 2H, Ar ortho Cl; 7.85, m, 2H,Ar ortho CO; 8.07, d, 2H, Ar ortho SO₂.

18c) Ethyl5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylateXXV (R=p-R₁ =R₂ =H, n=1, A=a, R₃ =Et) (method P)

A solution of 500 mg (0.95 mmoles) of the above compound 18b in 20 ml ofethyl acetate containing 2 moles of gaseous HCl per liter is stirred for2 h at 25° C. and then evaporated to dryness. The residue is taken up inisopropyl ether and the insoluble matter is recovered (weight=0.32g-yield=77%) and has the formula ##STR65## Compound 1d

The physicochemical characteristics of this derivative have already beenreported in Example 1. It can be saponified by method G to give compound1.

EXAMPLE 19 Preparation of ethyl5-(2-(N-ethoxycarbonylparachlorobenzenesulphonamido)ethyl)-2,3-dihydro-2-benzofurancarboxylateXXI (R=p-Cl--C₆ H₄, R₇ =EtOCO, R₂ =H, R₅ =Et, n=1) (compound 2c) (methodM) (synthesis scheme I)

A mixture of 1 g (2.02 mmoles) of ethyl5-(N-ethoxycarbonylparachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylate(cf. compound 2b, Example 2) in 60 ml of acetic acid containing 3 dropsof perchloric acid is hydrogenated in a stainless steel reactor under apressure of 4 bars in the presence of 200 mg of palladium deposited oncharcoal (10%) as the catalyst. After stirring for 24 h at 25°C., thereactor is purged with nitrogen, the catalyst is filtered off andrecovered and the filtrate is poured onto crushed ice, keeping the pH atabout 2-3 by adding a saturated solution of sodium bicarbonate. Themixture is extracted with ethyl acetate and the extract is washed with adilute solution of sodium bicarbonate and then with water and withsaline water and dried over sulphate. The residue (920 mg) is purifiedon a silica (20 g) column eluting with an 85/15 hexane/ethyl acetatemixture. The fractions containing the expected derivative are combinedand evaporated to dryness to give 700 mg (yield=72%) of compound 2c inthe form of a slightly yellow coloured viscous oil of formula ##STR66##Compound 2c

The physicochemical characteristics (IR and NMR spectra) of thiscompound have already been given in Example 2.

EXAMPLE 20 Preparation of ethyl6-(parachlorobenzenesulphonamidoacetyl)-2-chromancarboxylate XXV(R=p-Cl--C₆ H₄, R₁ =R₂ =H, R₃ =Et, n=1, A=g and for I X=CO) (compound20) (synthesis scheme I)

20a) Ethyl6-(N-tert.-butyloxycarbonyl-parachlorobenzenesulphonamidoacetyl)-2-chromancarboxylateXXIV (R=p-Cl--C₆ H₄, R₇ =COO-tBu, R₂ =H, R₅ =Et, n=1, A=g) (compound20a) (method I).

Using the sodium salt ofN-tert.-butyloxycarbonyl-parachlorobenzenesulphonamide XX (R=p-Cl--C₆H₄, R₇ =t-BuOCO--) prepared according to Example 18a and subjecting 5.51g (17.5 mmoles) of this compound to a condensation reaction with 5 g(15.2 mmoles) of ethyl 5-bromoacetyl-2-chromancarboxylate in accordancewith the process described in Example 18b, compound 20a is obtained in ayield of 99%; this compound is used in the crude form in the followingstep and has the formula ##STR67## Compound 20a

empirical formula: C₂₅ H₂₈ ClNO₈ S

molecular weight: 523.99

broken white powder

melting point slow: 60° C.

IR (KBr): √SO₂ 1170-1350; √CO 1700; √COOEt and NCOOtBu 1755 cm⁻¹.

NMR (CDCl₃) δ: 1.3, m, 12H, C(CH₃)₃, OCH₂ CH₃ ; 3.40, q, 1H, OCHCH₂ Ar;3.63, q, 1H, OCHCH₂ Ar; 4.28, q, 2H, OCH₂ CH₃ ; 5.3, m, 3H, OCHCH₂ Ar,NHCH₂ CO; 6.97, d, 1H, Ar ortho O; 7.52, d, 2H, Ar ortho Cl; 7.84, m,2H, Ar ortho CO; 8.03, d, 2H, Ar ortho SO₂.

20b) Ethyl 6-parachlorobenzenesulphonamidoacetyl-2-chromancarboxylateXXV (R=p-Cl--C₆ H₄, R₁ =R₂ =H, R₃ =Et, A=g, n=1) (compound 20) (methodP).

By treating 8.2 g (15.2 mmoles) of the above compound 20a in thepresence of 100 ml of ethyl acetate containing 2 moles of gaseous HClper liter in accordance with Example 18c, and after recrystallization ofthe crude residue from 100 ml of a 90/10 isopropanol ether/ethyl acetatemixture, compound 20 is prepared in a yield of 73%, this compound havingthe formula ##STR68## Compound 20

empirical formula: C₂₀ H₂₀ ClNO₆ S

molecular weight: 437.90

pulverulent white crystals

melting point: 150° C.

IR (KBr): √SO₂ N 1160-1350; √CO 1690; √COOEt 1740, √NH 3300 cm⁻¹.

NMR (CDCl₃) δ: 1.24, t, 3H, CH₃ ; 2.18, m, 2H, OCHCH₂ Ar; 2.73, m, 2H,OCHCH₂ CH₂ Ar; 4.20, q, 2H, OCH₂ CH₃ ; 4.35, s, 2H, NHCH₂ CO; 4.78, t,1H, OCHCH₂ CH₂ Ar; 6.06, s, 1H, NH; 6.90, d, 1H, Ar ortho O; 7.40, d,2H, Ar ortho Cl; 7.58, m, 2H, Ar ortho CO; 7.79, d, 2H, Ar ortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: hexane/ethyl acetate: 50/50

Rf: 0.35

solubility: soluble in DMSO to give a 25% solution insoluble in water.

EXAMPLE 21 Preparation of6-(parachlorobenzenesulphonamidoacetyl)-2-chromancarboxylic acid IX(R=p-Cl--C₆ H₄, R₂ =H, n=1, A=g) (compound 21) (synthesis scheme I)(method G)

Starting from 3.9 g (8.9 mmoles) of ethyl6-parachlorobenzenesulphonamidoacetyl-2-chromancarboxylate (compound 20)and saponifying this ester in accordance with the process described inExample 1e and purifying the product on a column of 20 g ofsilica/eluant CHCl₃ /MeOH/AcOH 95/4.4/0.5, compound 21 is prepared witha yield of 40%, this compound having the formula ##STR69## Compound 21

empirical formula: C₁₈ H₁₆ ClNO₆ S

molecular weight: 409.84

white crystals

melting point: 174°-175° C.

IR (KBr): √COOH 1740; √CO 1690; √NH 3300 cm⁻¹.

NMR (CDCl₃) δ: 2.18, m, 2H, OCHCH₂ CH₂ Ar; 2.76, m, 2H, OCHCH₂ CH₂ Ar;4.32, s, 2H, NHCH₂ CO; 4.74, t, 1H, OCHCH₂ Ar; 6.23, s, 1H, NH; 6.90, d,1H, Ar ortho O; 7.40, d, 2H, Ar ortho Cl; 7.57, m, 2H, Ar ortho CO;7.78, d, 2H, Ar ortho SO₂.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic acid 80/18/02

Rf: 0.35

solubility: soluble in DMSO to give a 25% solution insoluble in water.

EXAMPLE 22 Preparation of5-(benzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylic acid IX(R=C₆ H₅, R₂ =H, n=1, A=a) and for I (X=CO, R₁ =R₃ =H) (compound 22)(synthesis scheme I).

22a) Ethyl5-(benzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylate VII(compound 22a) (R=C₆ H₅, R₂ =H, A=a, R₅ =Et) (method D)

Treating 3 g (10.4 mmoles) of ethyl5-(aminoacetyl)-2,3-dihydro-2-benzofurancarboxylate hydrochloride(compound 1c) with 2.8 g (15.7 mmoles) of benzenesulphonyl chloride inaccordance with operating method 1d, compound 22a is obtained in a yieldof 75% after recrystallization from isopropyl alcohol; this compound hasthe formula ##STR70## Compound 22a

empirical formula: C₁₉ H₁₉ NO₆ S

molecular weight: 389.43

broken white crystals

melting point: 109° C.

NMR (CDCl₃) δ: 1.30, t, 3H, OCH₂ CH₃ ; 3.53, q, 1H, OCHCH₂ Ar; 3.81, q,1H, OCHCH₂ Ar; 4.27, q, 2H, OCH₂ CH₃ ; 4.63, d, 2H, NHCH₂ CO; 5.93, q,1H, OCHCH₂ Ar; 6.71, t, 1H, NH; 7.01, d, 1H, Ar ortho O; 7.62 to 8.10,m, 7H, Ar.

22b) 5-Benzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylic acidIX (compound 22) (R=C₆ H₅, R₂ =H, n=1, A=a) (method G)

Carrying out the reaction as in Example 1e but starting from 2.95 g(7.57 mmoles) of the above ester 22a, compound 22 is obtained in a yieldof 40% after purification on a silica column; this compound has theformula ##STR71## Compound 22

empirical formula: C₁₇ H₁₅ NO₆ S

molecular weight: 361.37

broken white crystals

melting point: 179° C.

IR (KBr): √SO₂ 1180-1346; √CO 1690; √COOH 1750; √NH 3300 cm⁻¹

NMR (CDCl₃) δ: 3.53, q, 1H, OCHCH₂ Ar; 3.81, q, 1H, OCHCH₂ Ar; 4.63, d,2H, NHCH₂ CO; 5.93, q, 1H, OCHCH₂ Ar; 6.71, t, 1H, NH; 7.01, d, 1H, Arortho O; 7.62 to 8.10, m, 7H, Ar.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic acid 80/18/02

Rf: 0.30

solubility: soluble in DMSO to give a 25% solution insoluble in water.

EXAMPLE 23 Preparation of5-paramethoxybenzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylicacid IX (R=p-CH₃ O--C₆ H₄ --, R₂ =H, n=1, A=a) and for I (R₁ =R₃ =H andX=CO) (compound 23) (synthesis scheme I) (method D)

23a) Ethyl5-paramethoxybenzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylateVIII (compound 23a) (R=p-CH₃ O--C₆ H₄ --, R₂ =H, A=a, R₅ =Et, n=1)

Reacting 3 g (10.4 mmoles) of ethyl5-aminoacetyl-2,3-dihydro-2-benzofurancarboxylate hydrochloride(compound 1c) with 3 g (14.5 mmoles) of paramethoxybenzenesulphonylchloride in accordance with the process described in Example 1d,compound 23a is obtained quantitatively, this compound having theformula ##STR72## Compound 23a

empirical formula: C₂₀ H₂₁ NO₇ S

molecular weight: 421.46

amber viscous oil

23b)5-Paramethoxybenzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylicacid IX (compound 23) (R=p-CH₃ O--C₆ H₄ --, R₂ =H, n=1, A=a) (method G)

Carrying out the reaction in the same way as in Example 1e but startingfrom 4.42 g (10.4 mmoles) of the above crude ester (compound 23a),compound 23 is obtained in a yield of 35% after recrystallization fromchloroform; this compound has the formula ##STR73## Compound 23

empirical formula: C₁₈ H₁₇ NO₇ S

molecular weight: 391.40

white crystals

melting point: 162° C.

IR (KBr): √SO₂ 1160-1350; √CO 1695; √COOH 1755; √NH 3300 cm⁻¹ NMR(CDCl₃) δ: 6.95, m, 3H, Ar ortho O; 7.65 to 7.75, m, 4H, Ar.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic acid 80/18/02

Rf: 0.30

solubility: soluble in DMSO to give a 30% solution

EXAMPLE 245-(Pentafluorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid IX (R=C₆ F₅, R₂ =H, n=1, A=a) and for I (X=CO, R₁ =R₃ =H) (compound24) (synthesis scheme I) (method D)

24a) Ethyl5-(pentafluorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylateVIII (R=C₆ F₅, R₂ =H, n=1, R₅ =Et, A=a).

Starting from 3 g (10.4 mmoles) of ethyl5-(aminoacetyl)-2,3-dihydro-2-benzofurancarboxylate hydrochloride(compound 1c) and subjecting this to a condensation reaction inaccordance with Example 1d with 4 g (15 mmoles) ofpentafluorobenzenesulphonyl chloride, 1.30 g (yield 26%) of compound 24aare obtained after purification on silica and crystallization fromisopropyl ether; this compound has the formula ##STR74## Compound 24a

empirical formula: C₁₉ H₁₄ F₅ NO₆ S

molecular weight: 479.38

yellow crystals

melting point: 127° C.

24b)5-Pentafluorobenzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylicacid (compound 24)

A solution of 1.1 g (2.3 mmoles) of the above ester in a methanol/watermixture containing sodium bicarbonate is saponified in accordance withthe process described in Example 1e to give 0.55 g (yield 58%) ofcompound 24 after purification on silica and crystallization fromisopropyl ether; this compound has the formula ##STR75## Compound 24

empirical formula: C₁₇ H₁₀ F₅ NO₆ S

molecular weight: 451.32

broken white crystals

melting point: 200° C. instantaneous

IR (KBr): √SO₂ 1180-1330; √CO 1690; √COOH 1735; √NH 3240 cm⁻¹

NMR (CDCl₃) δ: 3.54, q, 1H, OCHCH₂ Ar; 3.82, q, 1H, OCHCH₂ Ar; 4.93, s,2H, NHCH₂ CO; 5.54, q, 1H, OCHCH₂ Ar; 7.04, d, 1H, Ar ortho O; 7.73, s,1H, NH; 7.98, m, 2H, Ar ortho CO.

TLC: silica gel 60 Merck F 254

eluant: chloroform/methanol/acetic acid 80/18/02

Rf: 0.42

solubility: soluble in DMSO to give a 20% solution insoluble in water.

EXAMPLE 25 (dl)-Lysine5-parachlorobenzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylatetrihydrate I (R=p-Cl--C₆ H₄ --, R₁ =R₂ =R₃ =H, n=1, A=a, X=CO) ##STR76##3H₂ O) (compound 25)

A 50% solution of 6.65 g (22.7 mmoles) of dl-lysine is diluted with 18ml of water and then treated at 20° C. with 6.65 g (16.8 mmoles) of5-parachlorobenzenesulphonamidoacetyl-2,3-dihydro-2-benzofurancarboxylicacid (compound 1). The mixture becomes homogeneous and the salt thencrystallizes. The crystallization is completed by adding 150 ml ofisopropyl alcohol. After stirring for a further 1 hour, the salt isfiltered off, drained and dried and then recrystallized from 300 ml of a75/25 alcohol/water mixture to give compound 25 in a yield of 70%, thiscompound having the formula ##STR77## Compound 25

empirical formula: C₂₃ H₃₄ ClN₃ O₁₁ S

molecular weight: 596.05

broken white crystals

melting point slow: 130° C.

IR (KBr): √SO₂ 1173-1335-1360; √CO, COO⁻ wide band centred on 1600, √NH3300 cm⁻¹

solubility: soluble in water to give a 1% solution.

EXAMPLE 26 (dl)-Lysine6-(2-parachlorobenzenesulphonamidoethyl)-2-chromancarboxylate I(R=p-Cl--C₆ H₄ --, R₁ =R₂ =R₃ =H, n=1, A=g, X=CH₂) ##STR78## (compound26)

Carrying out the reaction in the same way as for the process describedin Example 25 but starting from 3.45 g (8.7 mmoles) of6-(2-parachlorobenzenesulphonamidoethyl)-2-chromancarboxylic acid,compound 26 is obtained directly (without recrystallization) in a yieldof 95%, this compound having the formula ##STR79## Compound 26

empirical formula: C₂₄ H₃₂ ClN₃ O₇ S

molecular weight: 542.05

white crystals

melting point: 214° C.

IR (KBr): √SO₂ 1180-1330-1355; √CO, COO⁻ wide band centred on 1600

solubility: soluble in water to give a 1% solution.

EXAMPLE 27 dl-Lysine6-(parachlorobenzenesulphonamidoacetyl)-2-chromancarboxylate I(R=p-Cl--C₆ H₄ --, R₁ =R₂ =R₃ =H, n=1, A=g, X=CO), ##STR80## (compound26)

Carrying out the reaction as described in Example 25 but starting from4.45 g (10.8 mmoles) of6-(2-parachlorobenzenesulphonamidoethyl)-2-chromancarboxylic acid and4.28 g of a 50% solution of dl-lysine in water, compound 27 is obtaineddirectly in a yield of 92%, this compound having the formula ##STR81##Compound 27

empirical formula: C₂₄ H₃₀ ClN₃ O₈ S

molecular weight: 556.034

broken white crystals

melting point: 226° C.

IR (KBr); √SO₂ 1180-1330-1355; √CO, COO⁻ wide band centred on 1610 cm⁻¹

solubility: soluble in water to give a 1% solution.

EXAMPLE 28 5-(Parachlorobenzenesulphonamidoacetyl)-2-indanecarboxylicacid I (R=p-Cl--C₆ H₄ --, R₁ =R₂ =R₃ =H, n=1, A=f, X=CO) (compound 28)(modified method P)

Using the operating method of Example 18a but starting from 15 g (50.5mmoles) of ethyl 5-bromoacetyl-2-indanecarboxylate prepared inaccordance with 9a and subjecting this to a condensation reaction with17.4 g (55 mmoles) of the sodium salt ofN-tert.-butyloxycarbonyl-parachlorobenzenesulphonamide prepared inaccordance with 18a, the synthesis intermediate of formula ##STR82## isobtained in a quantitative yield; this intermediate is not isolated andis hydrolysed for 1 h at 60° C. with 250 ml of an aqueous solution ofconcentrated hydrochloric acid.

This reaction mixture is diluted with 600 ml of water and theprecipitate formed is filtered off, drained, washed with water, driedand recrystallized from boiling ethyl acetate to give 6 g (yield=70%) ofwhite crystals of formula ##STR83## Compound 28

empirical formula: C₁₈ H₁₆ ClNSO₆

molecular weight: 393.845

white crystals

melting point: 150° C. then recrystallizes and remelts at 181° C.

IR (KBr): √SO₂ 1163-1350; √CO and COOH 1700; √NH 3290 cm⁻¹

NMR (DMSO d₆): from 3.1 to 3.35, m, 5H, CH₂ CHCH₂ ; 4.48, d, 2H, NCH₂CO; 7.34, d, 1H, Ar meta of CO; 7.64, d, 2H, Ar ortho Cl; 7.84, d, 2H,Ar ortho SO₂ ; 7.6 to 7.8, m, 2H, Ar ortho CO; 8.18, t, 1H, NH; 12.4, s,1H, COOH.

TLC: silica gel Merck F 254

eluant: chloroform/methanol/acetic

acid: 90/09/01

Rf=0.46

insoluble in water; soluble in DMSO to give a 15% solution.

EXAMPLE 29 dl-Lysine5-(parachlorobenzenesulphonamidoacetyl)-2-indanecarboxylate I(R=p-Cl--C₆ H₄ --, R₁ =R₂ =R₃ =H, n=1, A=f, X=CO), ##STR84## (compound29)

Carrying out the reaction as described in Example 25 but starting from 5g (12.5 mmoles) of5-(parachlorobenzenesulphonamidoacetyl)-2-indanecarboxylic acid and 3.42g of a 50% aqueous solution of lysine, 6 g of crude salt are obtainedwhich are recrystallized from a 60/40 ethanol/water solution to givecompound 29 in a yield of 66%, this compound having the formula##STR85## Compound 29

empirical formula: C₂₄ H₃₀ ClN₃ O₇ S

molecular weight: 540.035

broken white crystals

melting point with decomposition: 165° C.

IR (KBr): √SO₂ 1160-1350; √CO 1690; √NH 3300 cm⁻¹

soluble in water to give a 0.5% solution.

BIOLOGICAL EXPERIMENTS

The compounds of the present invention of general formula I and theirtherapeutically acceptable acid salts have valuable pharmacodynamicproperties. These compounds are highly anti-aggregant by selectiveinhibition of the action of thromboxane A₂. These compounds are activeboth at the platelet level and at the endothelial tissue level. Thesecompounds oppose the platelet aggregation induced by thethromboxamimetic compound U.46619 and the platelet aggregation inducedby arachidonic acid. This action is revealed in in vitro or ex vivotests. These compounds can be used for preventive purposes incardiovascular ischaemia and as adjuvant treatment for thromboses or inmyocardial infarction.

1) Toxicology

The chemical compounds described above were subjected to toxicitychecks. This study was carried out on conventional mice weighing from 20to 22 g. The compounds of general formula I were administeredintraperitoneally. At 500 mg per kilo, compounds 1, 2 and 3, given byway of non-limiting example, proved to be atoxic and not a singlefatality is observed at this dose.

3) Pharmacological Study

The pharmacological experiments to which the chemical molecules whichare the subject of the present invention were subjected enabled avaluable activity on the cardiovascular system to be shown in both invivo and in vitro tests. The compounds of general formula I provedcapable of reducing the aggregant and vasoconstrictive effects ofcompound U.46619 at remarkably low doses.

a) In vitro action:

Blood is taken from white male New Zealand rabbits which have notreceived any treatment capable of disrupting the platelet functions.

After having allowed the first drops to flow freely, the blood iscollected in plastic tubes containing 3.8% (wt/v) trisodium citrate 5.5H₂ O, the citrate/blood ratio being 1 volume of citrate per 9 volumes ofblood.

The blood platelet aggregation study is carried out starting fromplasmas rich in platelets obtained by centrifuging the above bloodsamples at low speed. It is measured with the aid of a Mustardaggregometer at a wavelength of 609 nm with a stirring speed of 1,100revolutions/min.

The products to be studied are dissolved in polyethylene glycol 300 andpre-incubated for 1 min at 37° C. under a volume of 10 microliters, in amixture of 300 microliters of plasma rich in platelets and 90microliters of Tyrode's solution without calcium, pH=7.4. (Correspondingcontrols are produced by pre-incubating the vehicle on its own insteadof solutions of products to be studied).

The blood platelet aggregation is initiated by the addition either ofU.46619 (final concentrations: 1.05 to 2.44 micromoles) or ofarachidonic acid (final concentrations: 50 to 100 micromoles).

Starting from the parameter of the maximum percentage aggregation, theanti-aggregant activity of a product is calculated using the formula:##EQU1##

One curve: anti-aggregant activity=f (final concentration) is plottedfor each product and the 50% inhibitory concentration determined fromthe graph.

In the case of aggregation with U.46619, the IC₅₀ are given in Table Ifor compounds 1, 2, 3, 7 and 11 by way of non-limiting example:

                  TABLE I                                                         ______________________________________                                        Compound      IC.sub.50                                                       ______________________________________                                        1             6 × 10.sup.-7 M                                           2             5 × 10.sup.-7 M                                           3             5 × 10.sup.-6 M                                           7             5 × 10.sup.-7 M                                           11            2 × 10.sup.-6 M                                           ______________________________________                                    

The percentage inhibition of the aggregation with arachidonic acid isgiven in Table II for compounds 2 and 3 by way of non-limiting examples:

                  TABLE II                                                        ______________________________________                                                   Final concentration                                                                         % inhibition of                                      Compound   of compound studied                                                                         platelet aggregation                                 ______________________________________                                        2          10.sup.-4 M   -100%                                                           10.sup.-5 M   -79%                                                            5.10.sup.-6 M -31%                                                 3          10.sup.-4 M   -86%                                                            5.10.sup.-5 M -78%                                                            10.sup.-5 M    -7%                                                 ______________________________________                                    

b) Ex vivo action: inhibition of anti-aggregant effects using U.46619 inrabbits.

Because of their powerful activity in vitro, the anti-aggregant effectsex vivo were studied in rabbits. The substances of general formula I,which are the subject of the present invention, are administered orallyas a 1% suspension in carboxymethylcellulose to natural male New Zealandrabbits weighing 2.5 to 3 kg after going without nourishment for about18 h. Blood samples were taken by cardiac puncture at time 0 and after90 min. The aggregant U.46619 was used under the same conditions asabove and the measurement of the aggregation was carried out using thesame technique.

The results are expressed in Table III in terms of percentage inhibitionof the maximum amplitude of the aggregation curve at t=+90 min relativeto the control curve at t=0 and are given for compounds 2 and 3 by wayof non-limiting example:

                  TABLE III                                                       ______________________________________                                                       dose    % inhibition of                                        Compounds I    mg/kg   aggregation                                            ______________________________________                                        2               5      -64%                                                                  10      -98%                                                   3               5      -43%                                                                  10      -74%                                                   ______________________________________                                    

3) Therapeutic Applications

Having regard for their pharmacological activity, the derivatives of thepresent invention can be used in human and animal therapy for thetreatment of cardiovascular disorders. The compounds inhibit plateletaggregation and the vasoconstrictive effects due to an activation ofthromboxane A₂ at the platelet and the vascular tissue level, acting byantagonism of its receptors on these cells. The compounds of the presentinvention are active on aggregation induced by collagen and arachidonicacid and to a lesser degree on that induced by PAF and ADP. Theseproperties therefore make it possible to reduce myocardial ischaemiaand, in particular, restenoses after angioplasty or after injection ofstreptokinase. Because of their good bioavailability by the oral route,they can be used to treat cerebral or peripheral (arteritic) ischaemiasand atherosclerosis. These compounds also have a secondary indication inthe treatment of asthma, bacteriemal shock and glomerulonephrites and invirus diseases and also enable the disemination of cancer cells to becombatted.

The compounds of the present invention are used to prepare medicamentswhich can be administered to warm-blooded animals or to man.

The administration can be effected orally, parenterally or rectally andeach dose consists of an inert pharmaceutical adjuvant facilitating thepreparation and the absorption of the medicament and of the activeprinciple, which can be combined with another. These medicaments can bein the form of tablets, capsules, suspensions, emulsions, syrups,suppositories, solutions or analogous preparations. The active principleis administered in an average dose of between 0.5 and 25 mg/kg bodyweight.

Three preparations are given by way of non-limiting example. Theingredients, and others, can be introduced in other proportions withoutmodifying the scope of the invention.

EXAMPLE 30 Injectable Solution

    ______________________________________                                        1 injection flask make of inactinic glass containing                                                       20    mg                                         pulverulent sodium 5-(2-parachlorobenzenesulphonamido-                        acetyl)-2,3-dihydro-2-benzofurancarboxylate                                   1 sealed ampoule containing an apyrogenic                                                                  2     ml                                         sterile solution of distilled water + NaCl q.s.                               a final isotonic solution of                                                  ______________________________________                                    

Extemporaneous preparation of the solution before injection.

EXAMPLE 31 Tablets

    ______________________________________                                        5-(2-parachlorobenzenesulphonamidoacetyl)-                                                             100  mg                                              2,3-dihydro-2-benzofurancarboxylic acid                                       lactose                  60 mg                                                corn starch              20 mg                                                polyvinylpyrrolidone     18 mg                                                magnesium stearate        2 mg                                                tablet weighing          200 mg                                               ______________________________________                                    

EXAMPLE 32 Suppositories

    ______________________________________                                        5-(2-parachlorobenzenesulphonamidoacetyl)-2,3-                                dihydro-2-benzofurancarboxylic acid                                                                       100    mg                                         suppository base (cocoa butter) q.s.                                                                      2.5    g                                          ______________________________________                                         to be stored in the absence of light, heat and moisture.

We claim:
 1. New sulphonamide derivatives of carbocyclic orbenzo-heterocyclic acids of general formula I ##STR86## in which theradicals and substituents are defined as follows: R represents astraight-chain or branched lower alkyl containing 1 to 9 carbon atoms,or phenyl or naphthyl radicals which are unsubstituted or substituted byone or more groups: lower alkyl (1 to 4 C), halogen, lower alkoxy (1 to4 C), nitro, amino, dialkylamino or trifluoromethyl, or a thiophenylradical;R₁ represents hydrogen or a straight-chain or branched loweralkyl (1 to 4 C) or benzyl; R₂ represents hydrogen or a straight-chainor branched lower alkyl (1 to 6 C), a phenyl group which isunsubstituted or substituted by a chlorine or a methoxy or an aralkylgroup containing from 7 to 9 carbon atoms; R₃ represents hydrogen or astraight-chain or branched lower alkyl (1 to 6 C); --X-- represents adivalent functional radical chosen from the following: ##STR87## withthe proviso, however, that X differs from --CH₂ -- when --A-- representsdivalent radicals a, b, d and e below, --A-- represents a benzo-cyclicor benzo-heterocyclic divalent radical chosen from the following: (a-e)and (h-j) ##STR88## and n is 1 to 4 inclusive, the hydrated forms ofacids of general formula I and the therapeutically acceptable organic orinorganic salts of I, it is being possible for the compounds of generalformula I to be in the form of a racemic mixture or to be isolated inthe form of enantiomers, diastereoisomers or their mixture in anyproportions.
 2. Compounds in accordance with claim 1 wherein X is --C=O.3. Compounds in accordance with claim 1 wherein --A-- is ##STR89## 4.Compounds in accordance with claim 3 in which X is --C=O.
 5. Compoundsin accordance with claim 3 wherein R is a 4-chlorophenyl radical. 6.Compounds in accordance with claim 1 wherein X is --CH₂ --.
 7. Compoundsin accordance with formula I of claim 1 wherein R is a 4-chlorophenylradical.
 8. Compounds in accordance with claim 1 wherein X is C=O, A is(a), R₁ and R₂ are each hydrogen atoms and n is
 1. 9. The sulphonamidederivative of claim 1 where the therapeutically acceptable organic orinorganic salt is selected from the group consisting of sodium, calcium,zinc, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,tris(2-hydroxyethyl)ammonium and morpholinium.
 10. Compound according toclaim 1, characterized in that it is chosen from the followingcompounds:5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid5-(2-parachlorobenzenesulphonamido-1-hydroxyethyl)-2,3-dihydro-2-benzofurancarboxylicacid5-(2-parachlorobenzenesulphonamido-1-hydroxyiminoethyl)-2,3-dihydro-2-benzofurancarboxylicacid5-(2-parachlorobenzenesulphonamido-1-methoxyiminoethyl)-2,3-dihydro-2-benzofurancarboxylicacid5-(N-methyl-parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid5-(α-methyl-parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid5-(2-parachlorobenzenesulphonamido-1-hydroxypropyl)-2,3-dihydro-2-benzofurancarboxylicacidethyl-5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylate5-(2-parachlorobenzenesulphonamidoacetyl)-1,3-benzodioxole-2-carboxylicacid 6-(2-parachlorobenzenesulphonamidoethyl)-2-chromancarboxylic acid6-(parachlorobenzenesulphonamidoacetyl)-2-chromancarboxylic acidethyl-6-(parachlorobenzenesulphonamidoacetyl)-2-chromancarboxylate5-(benzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylic acid5-(paramethoxybenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid5-(pentafluorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylicacid lysine5-(parachlorobenzenesulphonamidoacetyl)-2,3-dihydro-2-benzofurancarboxylatlysine 6-(2-parachlorobenzenesulphonamidoethyl)-2-chromancarboxylatelysine 6-(parachlorobenzenesulphonamidoacetyl)-2-chromancarboxylate. 11.Pharmaceutical compositions characterized in that they contain, asactive principle, at least one compound defined according to claims 1 or10 in combination with an inert pharmaceutical carrier.
 12. The methodof treating a patient suffering from a disorder of the cardiovascularsystem which comprises administering to said patient an amount of atleast one compound in accordance with claim 1 or 10 which is effectiveto inhibit thromboxane receptors.
 13. Process for the preparation ofchemical compounds according to claim 1 where A differs from b, e, h andj, characterized in that a benzo-cyclic or benzo-heterocyclic ester offormula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure III ##STR90##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature varying from -5° C. to+50° C. so as to obtain the compound IVa of formula ##STR91## whichitself is subjected to a condensation reaction with sodium nitride in anaqueous-alcoholic mixture at a temperature of between +10° C. and +50°C. to give the compound of formula: ##STR92## which is selectivelyreduced by hydrogen in a lower alcohol containing an aqueous solution ofa strong acid in the presence of a hydrogenation catalyst deposited onan inert support to give, at a temperature of between +10° C. and +50°C., the aminoketoester hydrochloride of formula VI: ##STR93## which isitself subjected to a condensation reaction with a suitably substitutedsulphonyl halide of formula:

    R--SO.sub.2 Z                                              VII

in a basic organic solvent at a temperature of between -15° C. and +40°C., to give the compound I where X=CO and R₁ =H, and R₃ differs from H,of formula VIII: ##STR94## and, finally, this ester is saponified withan aqueous alkaline solution in the presence of a miscible organicsolvent at a temperature of between +10° C. and the boiling point of themixture, to give, after acidification, the acid compound I where X=CO,R₁ =H and R₃ =H, of formula IX ##STR95## and R₅ =R₃ with the exceptionof H; Y and Y₁ represent a chlorine or a bromine and Z represents afluorine or a chlorine or a bromine.
 14. Process in accordance withclaim 13 wherein said compatible solvent is methylene chloride or1,2-dichloroethane, said Lewis acid is aluminum chloride, said strongacid is hydrochloric acid, said hydrogenation catalyst is palladiumdeposited on charcoal, said sulphonyl halide is a fluoride, chloride orbromide, said aqueous alkaline solution is a solution of sodium orpotassium hydroxide, and said miscible organic solvent is selected fromthe group consisting of methanol, ethanol, dioxane and tetrahydrofuran.15. Process for the preparation of chemical compounds according to claim1 where A differs from b, e, h and j, characterized in that abenzo-carbocyclic or benzo-heterocyclic ester of general formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure IIIa ##STR96##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature of between -5° C. and +50°C. so as to obtain compound IVb of formula ##STR97## which is itselfreduced by an alkaline metal borohydride so as to obtain the derivativeXXIX of formula ##STR98## to lead, by basic hydrolysis, to the sodiumsalt of the aminohydroxy acid of formula XXX ##STR99## and finally, bysubjecting a suitably substituted sulphonyl halide of formula RSO₂ Z toa condensation reaction with the crude sodium salt of XXX obtained abovein the same aqueous-organic phase at a pH of between 11 and 13 and at atemperature of between 0° and +40° C., to give the compound I where R₃=H and X=CHOH, of formula XXVII ##STR100## in which the radicals ingeneral formulae IVb, XXIX, XXX and XXVII are defined as follows: Rrepresents a straight-chain or branched lower alkyl containing 1 to 9carbon atoms, or phenyl or naphthyl radicals that are unsubstituted orsubstituted with one or more lower alkyl containing 1 to 4 carbon atoms,halogen, lower alkoxy containing 1 to 4 carbon atoms, nitro, amino,dialkylamino, trifluoromethyl or a thiophenyl radical; R₁ representshydrogen or a straight-chain or branched lower alkyl containing 1 to 4carbon atoms or benzyl; R₂ represents hydrogen a straight-chain orbranched lower alkyl containing 1 to 6 carbon atoms or a phenyl groupwhich is unsubstituted or substituted by chlorine methoxy, or an aralkylgroup containing 7 to 9 carbon atoms; R₃ represents a straight-chain orbranched lower alkyl containing 1 to 6 carbon atoms; R₅ =R₃ R₈represents a straight-chain lower alkyl radical containing 1 to 6 carbonatoms; n is 1 to 4 inclusive; Y represents chlorine or bromine; and Zrepresents fluorine, chlorine or bromine.
 16. Process for thepreparation of chemical compounds according to claim 1 where A differsfrom b, e, h and j, characterized in that a benzocyclic orbenzo-heterocyclic ester of formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure III ##STR101##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature varying from -5° C. to+50° C. so as to obtain the compound IVa of formula ##STR102## whichitself is subjected to a condensation reaction with sodium nitride in anaqueous-alcoholic mixture at a temperature of between +10° C. and +50°C. to give the compound of formula ##STR103## which is reduced under anatmosphere of hydrogen in a lower alcohol containing an aqueous solutionof a strong acid in the presence of a hydrogenation catalyst depositedon an inert support to give, at a temperature of between +10° C. and+60° C. and in the course of several hours to give the compound offormula XII ##STR104## which is subjected to a condensation reactionwith a suitably substituted sulfonyl halide of formula

    R--SO.sub.2 Z

in a basic organic solvent at a temperature of between -15° C. and +40°C., to give compound I wherein X=CHOH and R₁ =H and R₃ differs from H,of formula XIII ##STR105## and finally this ester is saponified with anaqueous alkaline solution in the present of an alcoholic or etherealmiscible organic solvent at a temperature of between +10° C. and +60° C.to give, after acidification, the acid compound I where X=CHOH, R₁ =Hand R₃ =H, of formula XIV ##STR106## wherein R₃ represents astraight-chain or branched lower alkyl containing 1 to 6 carbon atoms;R₅ =R₃ ; Y and Y₁ independently represent chlorine or bromine; Zrepresents fluorine, chlorine or bromine; R₂ represents hydrogen, astraight-chain or branched lower alkyl containing 1 to 6 carbon atoms ora phenyl group which is unsubstituted or substituted by chlorine,methoxy or an aralkyl group containing 7 to 9 carbon atoms; R representsa straight-chain or branched lower alkyl containing 1 to 9 carbon atoms,or phenyl or naphthyl radicals that are unsubstituted or substitutedwith one or more lower alkyl containing 1 to 4 carbon atoms, halogen,lower alkoxy containing 1 to 4 carbon atoms, nitro, amino, dialkylamino,trifluoromethyl or a thiophenyl radical; and n is 1 to 4 inclusive. 17.Process in accordance with claim 16 wherein said hydrogenation catalystis palladium deposited on charcoal, said sulphonyl halide is a fluoride,chloride or bromide, said basic organic solvent is pyridine, saidaqueous alkaline solution is sodium hydroxide or potassium hydroxide,said miscible organic solvent is selected from the group consisting ofmethanol, ethanol, dioxane and tetrahydrofuran, and wherein the progressof said reduction reaction is monitored by chromatography.
 18. Processfor the preparation of chemical compounds according to claim 1 where Adiffers from b, e, h and j, characterized in that a benzocyclic orbenzo-heterocyclic ester of formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure III ##STR107##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature varying from -5° C. to+50° C. so as to obtain the compound IVa of formula ##STR108## whichitself is subjected to a condensation reaction with sodium nitride in anaqueous-alcoholic mixture at a temperature of between +10° C. and +50°C., to give the compound of formula V ##STR109## which is selectivelyreduced by hydrogen in a lower alcohol containing an aqueous solution ofa strong acid in the presence of a hydrogenation catalyst deposited onan inert support to give, at a temperature of between +10° C. and +50°C., the aminoketoester hydrochloride of formula VI ##STR110## which isreduced under excess hydrogen pressure in the presence of a strong acidusing a hydrogenation catalyst in a carboxylic acid as the solventcarrying out the reaction at a temperature of between 20° C. and 90° C.under a hydrogen pressure of between 0.1 and 5 atmospheres to give thecompound XV in the form of the base or the salt of formula ##STR111##which is then subjected to a condensation reaction with a sulfonylhalide to give the compound I where R₁ =H and X=CH₂, or formula XVI, asaturated homologue of VIII and XIII ##STR112## which is saponified toprepare the derivatives IX and XIV, to give the compound I where R₁ =R₃+H and X=CH₂, of formula XVII ##STR113## wherein R₃ represents astraight-chain or branched lower alkyl containing 1 to 6 carbon atoms;R₅ =R₃ ; Y and Y₁ independently represent chlorine or bromine; n is 1 to4 inclusive; R represents a straight-chain or branched lower alkylcontaining 1 to 9 carbon atoms, or phenyl or naphthyl radicals that areunsubstituted or substituted with one or more lower alkyl containing 1to 4 carbon atoms, halogen, lower alkoxy containing 1 to 4 carbon atoms,nitro, amino, dialkylamino, trifluoromethyl or a thiophenyl radical; andR₂ represents hydrogen or a straight-chain or branched lower alkylcontaining 1 to 6 carbon atoms or a phenyl group which is unsubstitutedor substituted by chlorine, methoxy or an aralkyl group containing 7 to9 carbon atoms.
 19. Process according to claim 18 wherein said strongacid is sulphuric or perchloric acid.
 20. Process for the preparation ofchemical compounds according to claim 1 where A differs from b, e, h,and j, characterized in that a benzocyclic or benzo-heterocyclic esterof formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure III ##STR114##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature varying from -5° C. to+50° C. so as to obtain the compound IVa of formula ##STR115## which isreduced to give the halogenated compound having the formula XIX##STR116## which is subjected to a condensation reaction with the sodiumsalt, prepared in situ, of a suitably substituted secondary sulfonamideof formula XX

    R--SO.sub.2 NH--R.sub.7                                    XX

in an organic solvent at a temperature of between +5° C. and +60° C. togive the compound of formula XXI ##STR117## which derivative is thensaponified to give the equivalent saturated compound I where X=CH₂ andR₃ =H, of formula XXII ##STR118## and where R₇ represents either theradical R₁ other than hydrogen or the radical R₆ COO--, where R₆represents benzyl or a straight-chain or branched lower alkyl containingfrom 1 to 6 atoms inclusive; wherein R₃ represents a straight-chain orbranched lower alkyl containing 1 to 6 carbon atoms; R₅ =R₃ ; Y and Y₁independently represent chlorine or bromine; R₂ represents hydrogen or astraight-chain or branched lower alkyl containing 1 to 6 carbon atoms ora phenyl group which is unsubstituted or substituted by chlorine,methoxy or an aralkyl group containing 7 to 9 carbon atoms; n is 1 to 4inclusive; and R represents a straight-chain or branched lower alkylcontaining 1 to 9 carbon atoms, or phenyl or naphthyl radicals that areunsubstituted or substituted with one or more lower alkyl containing 1to 4 carbon atoms, halogen, lower alkoxy containing 1 to 4 carbon atoms,nitro, amino, dialkylamino, trifluoromethyl or a thiophenyl radical. 21.Process according to claim 20 wherein said organic solvent is selectedfrom the group consisting of dimethylformamide, dimethylacetamide,acetone, butanone, tetrahydrofuran and dioxane and R₆ is selected frommethyl, ethyl and tert.-butyl radicals.
 22. Process for the preparationof chemical compounds according to claim 1 where A differs from b, e, hand j, characterized in that a benzo-cyclic or benzo-heterocyclic esterof formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure III ##STR119##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature varying for -5° C. to +50°C. so as to obtain the compound IVa of formula ##STR120## which isreduced to give the halogenated compound having the formula XIX##STR121## which is subjected to a condensation reaction with the sodiumsalt, prepared in situ, of a suitably substituted secondary sulfonamideof formula XX

    R--SO.sub.2 NH--R.sub.7                                    XX

prepared in situ by the same process as to prepare compound XXI to givethe ketosulhpamidoester I where X=CO, of formula XXIV ##STR122## whichis saponified to give the compound XXV where R₁ =H and R₅ =R₃ anddiffers from H, which is then saponified to the acid as above, to givethe compound I where R₁ =R₃ =H and X=CO, of formula XXV ##STR123##wherein R₃ represents a straight-chain or branched lower alkylcontaining 1 to 6 carbon atoms; R₅ =R₃ ; R₇ is R₁ other than H or theradical R₆ COO--; R₆ represents benzyl or a straight-chain or branchedchain lower alkyl containing 1 to 6 carbon atoms; Y and Y₁ independentlyrepresent chlorine or bromine; n is 1 to 4 inclusive; R₂ representshydrogen or a straight-chain or branched lower alkyl containing 1 to 6carbon atoms or a phenyl group which is unsubstituted or substituted bychlorine, methoxy or an aralkyl group containing 7 to 9 carbon atoms;and R represents a straight-chain or branched lower alkyl containing 1to 9 carbon atoms, or phenyl or naphthyl radicals that are unsubstitutedor substituted with one or more lower alkyl containing 1 to 4 carbonatoms, halogen, lower alkoxy containing 1 to 4 carbon atoms, nitro,amino, dialkylamino, trifluoromethyl or a thiophenyl radical. 23.Process according to claim 22 wherein R₇ differs from COOR₆ and saidsaponification of the compound of formula XXIV is a directsaponification to give the compound I where X is CO, R₃ is H and R₁differs from H.
 24. Process according to claim 22 wherein R₇ is COO-tBuand said saponification of the compound of formula XXIV is preceded by acleavage of the group R₇ in a strong acid medium to give compound XXVwhere R₁ is H, R₅ is the same as R₃ and differs from H.
 25. Processaccording to claim 24 in which a crude mixture obtained after saidcondensation reaction is hydrolyzed by pouring it into a concentratedsolution of a strong acid, heating at a temperature from about 40° toabout 100° C. to give the compound I where R₁ is R₃ is hydrogen. 26.Process according to claim 25 in which said strong acid is hydrochloricacid and said temperature is between about 50° and 70° C.
 27. Processfor the preparation of chemical compounds according to claim 1 wherein Adiffers from b, e, h and j, characterized in that a benzo-cyclic orbenzo-heterocyclic ester of formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure III ##STR124##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature varying from -5° C. to+50° C. so as to obtain the compound IVa of formula ##STR125## which isreduced to give the halogenated compound having the formula XIX R1 ? ?##STR126## which is subjected to a condensation reaction with the sodiumsalt, prepared in situ, of a suitably substituted secondary sulfonamideof formula XX

    R--SO.sub.2 NH--R.sub.7                                    XX

to give the ketosulphamidoester I where X=CO, of formula XXIV ##STR127##which is reduced to give the sulfonamide homologue of formula XXI##STR128## and saponified to the corresponding acid I where X=CH₂ and R₃=H, of formula XXII wherein R₃ represents a straight-chain or branchedlower alkyl containing 1 to 6 carbon atoms; R₅ =R₃ ; Y and Y₁independently represent chlorine or bromine; n is 1 to 4 inclusive; R₂represents hydrogen or a straight-chain or branched lower alkylcontaining 1 to 6 carbon atoms or a phenyl group which is unsubstitutedor substituted by chlorine, methoxy or an aralkyl group containing 7 to9 carbon atoms; R represents a straight-chain or branched lower alkylcontaining 1 to 9 carbon atoms, or phenyl or naphthyl radicals that areunsubstituted or substituted with one or more lower alkyl containing 1to 4 carbon atoms, halogen, lower alkoxy containing 1 to 4 carbon atoms,nitro, amino, dialkylamino, trifluoromethyl or a thiophenyl radical; R₇is R₁ other than H or the radical R₆ COO--; and R₁ represents hydrogenor a straight-chain or branched lower alkyl containing 1 to 4 carbonatoms or benzyl.
 28. Process according to claim 27 wherein saidreduction step is under excess hydrogen pressure in the presence of astrong acid using a hydrogenation catalyst in a carboxylic acid as thesolvent, carrying out the reaction at a temperature of between 20° and90° C. under a hydrogen pressure of between 0.1 and 5 atmospheres. 29.Process according to claim 27 wherein said reduction step is by reducingcompound VI with a trialkylsilane in the presence of trifluoroaceticacid at a temperature of between +10° and +40° C.
 30. Process for thepreparation of chemical compounds according to claim 1 where A differsfrom b, e, h, and j, characterized in that a benzo-cyclic orbenzo-heterocyclic ester of formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure IIIa ##STR129##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature of between -5° C. and +50°C. so as to obtain compound IVb of formula ##STR130## is reduced to givea methylene group, to give the derivative XXXI of formula ##STR131##which is then saponified to lead to the sodium salt of the amino esterof formula XXXII ##STR132## which is condensed, without being isolated,with the sulfonyl halide of formula RSO₂ Z to give, after acidification,the compound I where X=CO and R₃ =H, of formula XXIII ##STR133## whereinR₃ represents a straight-chain or branched lower alkyl containing 1 to 6carbon atoms; R₅ =R₃ ; Y represents chlorine or bromine; Z representsfluorine, chlorine or bromine; R₁ represents hydrogen or astraight-chain or branched lower alkyl containing 1 to 4 carbon atoms orbenzyl; R₂ represents hydrogen or a straight-chain or branched loweralkyl containing 1 to 6 carbon atoms or a phenyl group which isunsubstituted or substituted by chlorine, methoxy or an aralkyl groupcontaining 7 to 9 carbon atoms; n is 1 to 4 inclusive; R represents astraight-chain or branched lower alkyl containing 1 to 9 carbon atoms,or phenyl or naphthyl radicals that are unsubstituted or substitutedwith one or more lower alkyl containing 1 to 4 carbon atoms, halogen,lower alkoxy containing 1 to 4 carbon atoms, nitro, amino, dialkylamino,trifluoromethyl or a thiophenyl radical; and R₈ represents a lowerstraight-chain alkyl radical containing 1 to 6 carbon atoms.
 31. Processfor the preparation of chemical compounds according to claim 1 where Adiffers from b, e, h and j, characterized in that a benzo-cyclic orbenzo-heterocyclic ester of formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure III ##STR134##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature varying from -5° C. to+50° C. so as to obtain the compound IVa of formula ##STR135## whichitself is subjected to a condensation reaction with sodium nitride in anaqueous-alcoholic mixture at a temperature of between +10° C. and +50°C. to give the compound of formula ##STR136## which is selectivelyreduced by hydrogen in a lower alcohol containing an aqueous solution ofa strong acid in the presence of a hydrogenation catalyst deposited onan inert support to give, at a temperature of between +10° C. and +50°C., the aminokestoester hydrochloride of formula VI ##STR137## isreduced by reducing compound VI with a trialkysilane in the presence oftrifluoroacetic acid at a temperature of between +10° C. and +40° C. togive the compound XV in the form of the base or the salt of formula##STR138## which is then subjected to a condensation reaction with asulfonyl halide to give the compound I where R₁ =H and X=CH₂, or formulaXVI, a saturated homologue of VIII and XIII ##STR139## which issaponified to prepare the derivatives IX and XIV, to give the compound Iwhere R₁ =R₃ =H and X=CH₂, of formula XVII ##STR140## wherein R₃represents a straight-chain or branched lower alkyl containing 1 to 6carbon atoms; R₅ =R₃ ; Y and Y₁ independently represent chlorine orbromine; R₂ represents hydrogen or a straight-chain or branched loweralkyl containing 1 to 6 carbon atoms or a phenyl group which isunsubstituted or substituted by chlorine, methoxy or an aralkyl groupcontaining 7 to 9 carbon atoms; R represents a straight-chain orbranched lower alkyl containing 1 to 9 carbon atoms, or phenyl ornaphthyl radicals that are unsubstituted or substituted with one or morelower alkyl containing 1 to 4 carbon atoms, halogen, lower alkoxycontaining 1 to 4 carbon atoms, nitro, amino, dialkylamino,trifluoromethyl or a thiophenyl radical; and n is 1 to 4 inclusive. 32.Process in accordance with claim 31 in which said trialkylsilane istriethylsilane.
 33. Process for the preparation of chemical compoundsaccording to claim 1 where A differs from be, e, h and j, characterizedin that a benzocyclic or benzo-heterocyclic ester of formula II

    H--A--COOR.sub.5                                           II

is reacted with a functional acyl halide of structure III ##STR141##under Friedel-Crafts conditions using a compatible solvent in thepresence of a Lewis acid and at a temperature varying from -5° C. to+50° C. so as to obtain the compound IVa of formula ##STR142## whichitself is subjected to a condensation reaction with sodium nitride in anaqueous-alcoholic mixture at a temperature of between +10° C. and +50°C. to give the compound of formula ##STR143## which is selectivelyreduced by hydrogen in a lower alcohol containing an aqueous solution ofa strong acid in the presence of a hydrogenation catalyst deposited onan inert support to give, at a temperature of between +10° C. and +50°C., the aminoketoester hydrochloride of formula VI ##STR144## which isitself subjected to a condensation reaction with a suitably substitutedsulfonyl halide of formula

    R--SO.sub.2 Z                                              VII

in a basic organic solvent at a temperature of between -15° C. and +40°C., to give the compound I where X=CO and R₁ =H, and R₃ differs from H,of formula VIII ##STR145## and, finally, this ester is saponified withan aqueous alkaline solution in the presence of a miscible organicsolvent; wherein R₃ represents a straight-chain or branched lower alkylcontaining 1 to 6 carbon atoms; R₅ =R₃ ; Y and Y₁ independentlyrepresent chloride or bromine; Z represents fluorine, chlorine orbromine; R₂ represents hydrogen or a straight-chain or branched loweralkyl containing 1 to 6 carbon atoms or a phenyl group which isunsubstituted or substituted by chlorine, methoxy or an aralkyl groupcontaining 7 to 9 carbon atoms; R represents a straight-chain orbranched lower alkyl containing 1 to 9 carbon atoms, or phenyl ornaphthyl radicals that are unsubstituted or substituted with one or morelower alkyl containing 1 to 4 carbon atoms, halogen, lower alkoxycontaining 1 to 4 carbon atoms, nitro, amino, dialkylamino,trifluoromethtyl or a thiophenyl radical; and n is 1 to 4 inclusive.